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Hong MX, Wang BW, Lo LH, Jayalath GED, Lin WT, Yang YL, Tseng SP, Chen YH, Tsai WC, Cheng WC, Liaw CC. Pseudopeptides of Marine Vibrio spp. from Taiwan and Their Combined Treatment Effects with Commercial Antibiotics. PLANTA MEDICA 2025. [PMID: 39933728 DOI: 10.1055/a-2536-8292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2025]
Abstract
Vibrio strains, identified by 16S rDNA, were isolated from the marine environment surrounding Taiwan, revealing diverse bioactive effects, such as iron-chelating and antimicrobial activities. Notably, the hierarchical clustering dendrogram of mass spectrum profiles of the Vibrio strains using matrix-assisted laser desorption ionization time-of-flight, in contrast to the phylogenetic tree based on 16S rDNA sequencing analysis, exhibited a strong correlation with their observed bioactivities. Within this set, global natural products social molecular network analysis by LC-HRMS/MS highlighted that three strains, Vibrio tubiashii DJW05 - 1, Vibrio japonicus DJW05 - 8, and Vibrio fortis DJW21 - 4, shared similar bioactive pseudopeptides in the same cluster. Subsequent chromatographical isolation and purification yielded an unprecedented unsaturated diketopiperazine, (Z)-3-(2-methylpropylidene)-2,3-dihydropyrrolo[1,2-a]pyrazine-1,4-dione (1: ), along with a series of diketopiperazines, and a potential new annotated pseudopeptide (2: ), as well as three pseudopeptides, including andrimid (10: ), moiramide B (11: ), and moiramide C (12: ), and several alkaloids from V. tubiashii DJW05 - 1. Further investigation into the combined applications of the major antimicrobial compound and commercial antibiotics revealed that andrimid (10: ) displayed significant inhibitory effects against gram-positive Staphylococcus aureus, and gram-negative Escherichia coli, Salmonella typhimurium, and Acinetobacter baumannii, but not Pseudomonas aeruginosa. Nevertheless, the potential for synergistic and additive effects of andrimid (10: ) with certain antibiotics remains, presenting valuable prospects for medicinal applications.
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Affiliation(s)
- Mao-Xuan Hong
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Bo-Wei Wang
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University/Academia Sinica, Kaohsiung, Taiwan
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
| | - Li-Hua Lo
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
| | | | - Wei-Tsen Lin
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yu-Liang Yang
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
| | - Sung-Pin Tseng
- Department of Medical Laboratory Science and Biotechnology, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yen-Hsu Chen
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Wan-Chi Tsai
- Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | - Chih-Chuang Liaw
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Pharmacognosy, Taiwan Medical University, Taipei, Taiwan
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2
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Luo W, Zheng X, Lin H, Fu L, Long L, Yu D, Chen Z, Yang M, Wang ZX. Discovery of intermolecular cascade annulation for dihydrobenzo[ b][1,8]naphthyridine-ylidene-pyrrolidinetriones. Chem Sci 2025; 16:4119-4126. [PMID: 39906387 PMCID: PMC11788672 DOI: 10.1039/d4sc07999j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 01/22/2025] [Indexed: 02/06/2025] Open
Abstract
Developing efficient procedures for the synthesis of combinations of pharmacophores continues to be a vital objective in synthetic science. Herein, we report an unprecedented family of dihydrobenzo[b][1,8]naphthyridine-ylidene-pyrrolidinetriones achieved by reacting ortho-halogenated quinolonechalcones with aminomaleimides under metal-free conditions. Among these compounds, several exhibit the potential to serve as fluorescent dyes for biological applications. Mechanistic investigations indicate that the reaction proceeds via a 1,4-Michael addition followed by an intermolecular cascade annulation, which involves aniline fragment transfer and SNAr processes. As far as we know, studies regarding the synthesis of dihydrobenzo[b][1,8]naphthyridine-ylidene-pyrrolidinetriones are rare. This discovery offers great inspiration for a feasible approach toward the creation of more complex and useful molecules.
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Affiliation(s)
- Wenjun Luo
- Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, Gannan Normal University Ganzhou 341000 P. R. China
| | - Xinghua Zheng
- Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, Gannan Normal University Ganzhou 341000 P. R. China
| | - Hehua Lin
- Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, Gannan Normal University Ganzhou 341000 P. R. China
| | - Li Fu
- School of Pharmacy, Jiangxi Provincial Key Laboratory of Tissue Engineering, Gannan Medical University Ganzhou 341000 China
| | - Lipeng Long
- Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, Gannan Normal University Ganzhou 341000 P. R. China
| | - Daohong Yu
- Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, Gannan Normal University Ganzhou 341000 P. R. China
| | - Zhengwang Chen
- Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, Gannan Normal University Ganzhou 341000 P. R. China
| | - Min Yang
- School of Pharmacy, Jiangxi Provincial Key Laboratory of Tissue Engineering, Gannan Medical University Ganzhou 341000 China
| | - Zhong-Xia Wang
- Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, Gannan Normal University Ganzhou 341000 P. R. China
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3
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Kirk A, Davidson E, Stavrinides J. The expanding antimicrobial diversity of the genus Pantoea. Microbiol Res 2024; 289:127923. [PMID: 39368256 DOI: 10.1016/j.micres.2024.127923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/07/2024] [Accepted: 09/26/2024] [Indexed: 10/07/2024]
Abstract
With the rise of antimicrobial resistance, there is high demand for novel antimicrobials to combat multi-drug resistant pathogens. The bacterial genus Pantoea produces a diversity of antimicrobial natural products effective against a wide range of bacterial and fungal targets. These antimicrobials are synthesized by specialized biosynthetic gene clusters that have unique distributions across Pantoea as well as several other genera outside of the Erwiniaceae. Phylogenetic and genomic evidence shows that these clusters can mobilize within and between species and potentially between genera. Pantoea antimicrobials belong to unique structural classes with diverse mechanisms of action, but despite their potential in antagonizing a wide variety of plant, human, and animal pathogens, little is known about many of these metabolites and how they function. This review will explore the known antimicrobials produced by Pantoea: agglomerins, andrimid, D-alanylgriseoluteic acid, dapdiamide, herbicolins, pantocins, and the various Pantoea Natural Products (PNPs). It will include information on the structure of each compound, their genetic basis, biosynthesis, mechanism of action, spectrum of activity, and distribution, highlighting the significance of Pantoea antimicrobials as potential therapeutics and for applications in biocontrol.
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Affiliation(s)
- Ashlyn Kirk
- Department of Biology, University of Regina, 3737 Wascana Parkway, Regina, Saskatchewan S4S0A2, Canada
| | - Emma Davidson
- Department of Biology, University of Regina, 3737 Wascana Parkway, Regina, Saskatchewan S4S0A2, Canada
| | - John Stavrinides
- Department of Biology, University of Regina, 3737 Wascana Parkway, Regina, Saskatchewan S4S0A2, Canada.
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4
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Butler MS, Vollmer W, Goodall ECA, Capon RJ, Henderson IR, Blaskovich MAT. A Review of Antibacterial Candidates with New Modes of Action. ACS Infect Dis 2024; 10:3440-3474. [PMID: 39018341 PMCID: PMC11474978 DOI: 10.1021/acsinfecdis.4c00218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 06/15/2024] [Accepted: 06/17/2024] [Indexed: 07/19/2024]
Abstract
There is a lack of new antibiotics to combat drug-resistant bacterial infections that increasingly threaten global health. The current pipeline of clinical-stage antimicrobials is primarily populated by "new and improved" versions of existing antibiotic classes, supplemented by several novel chemical scaffolds that act on traditional targets. The lack of fresh chemotypes acting on previously unexploited targets (the "holy grail" for new antimicrobials due to their scarcity) is particularly unfortunate as these offer the greatest opportunity for innovative breakthroughs to overcome existing resistance. In recognition of their potential, this review focuses on this subset of high value antibiotics, providing chemical structures where available. This review focuses on candidates that have progressed to clinical trials, as well as selected examples of promising pioneering approaches in advanced stages of development, in order to stimulate additional research aimed at combating drug-resistant infections.
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Affiliation(s)
- Mark S. Butler
- Centre
for Superbug Solutions and ARC Training Centre for Environmental and
Agricultural Solutions to Antimicrobial Resistance, Institute for
Molecular Bioscience, The University of
Queensland, St. Lucia, Queensland 4072, Australia
| | - Waldemar Vollmer
- Centre
for Superbug Solutions and ARC Training Centre for Environmental and
Agricultural Solutions to Antimicrobial Resistance, Institute for
Molecular Bioscience, The University of
Queensland, St. Lucia, Queensland 4072, Australia
| | - Emily C. A. Goodall
- Centre
for Superbug Solutions and ARC Training Centre for Environmental and
Agricultural Solutions to Antimicrobial Resistance, Institute for
Molecular Bioscience, The University of
Queensland, St. Lucia, Queensland 4072, Australia
| | - Robert J. Capon
- Centre
for Superbug Solutions and ARC Training Centre for Environmental and
Agricultural Solutions to Antimicrobial Resistance, Institute for
Molecular Bioscience, The University of
Queensland, St. Lucia, Queensland 4072, Australia
| | - Ian R. Henderson
- Centre
for Superbug Solutions and ARC Training Centre for Environmental and
Agricultural Solutions to Antimicrobial Resistance, Institute for
Molecular Bioscience, The University of
Queensland, St. Lucia, Queensland 4072, Australia
| | - Mark A. T. Blaskovich
- Centre
for Superbug Solutions and ARC Training Centre for Environmental and
Agricultural Solutions to Antimicrobial Resistance, Institute for
Molecular Bioscience, The University of
Queensland, St. Lucia, Queensland 4072, Australia
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Zhao Y, Zhang Y, Huang Y. Enantioselective Relay Coupling of Perfluoroalkyl and Vinylogous Ketyl Radicals. Angew Chem Int Ed Engl 2024; 63:e202409566. [PMID: 38865105 DOI: 10.1002/anie.202409566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/12/2024] [Accepted: 06/12/2024] [Indexed: 06/13/2024]
Abstract
β-Chiral carboxylic acids and their derivatives are highly valuable structural motifs in the fields of asymmetric synthesis and medicinal chemistry. However, the introduction of a sterically demanding sidechain to the β-carbon, such as an all-carbon quaternary center, remains a significant challenge in classical polar processes. Recently, N-heterocyclic carbene (NHC) mediated coupling reactions involving persistent ketyl radicals have emerged as a promising strategy to assemble highly crowded carbon-carbon bonds. Nevertheless, achieving enantioselectivity in these reactions remains highly challenging. In this work, we report our recent progress in controlling enantioselectivity for relay coupling of perfluoroalkyl and persistent vinylogous ketyl radicals. We developed a chiral bifunctional NHC-squaramide catalyst that achieves high facial selectivity in a critical bond-forming event involving the coupling of a congested tertiary carbon radical and vinylogous ketyl radical. Chiral carboxylates bearing an all-carbon quaternary center at the β-position can be prepared in good yield and excellent enantiomeric excess. Results from density functional theory (DFT) calculations and nuclear Overhauser effect (NOE) experiments indicate that the N,N'-diaryl squaramide motif adopts an unusual syn-syn conformation, enabling hydrogen bonding interactions with the enolate oxygen, thereby rigidifying the overall conformation of the transition state.
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Affiliation(s)
- Yuxin Zhao
- Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Yichi Zhang
- Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Yong Huang
- Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
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6
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Kirk A, Stavrinides J. Distribution and comparative genomic analysis of antimicrobial gene clusters found in Pantoea. Front Microbiol 2024; 15:1416674. [PMID: 39206372 PMCID: PMC11350110 DOI: 10.3389/fmicb.2024.1416674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 08/01/2024] [Indexed: 09/04/2024] Open
Abstract
Members of the bacterial genus Pantoea produce a variety of antimicrobial products that are effective against plant, animal, and human pathogens. To date, little is known about the distribution and evolutionary history of these clusters. We surveyed the public databases for the 12 currently known antibiotic biosynthetic gene clusters found across Pantoea strains to determine their distribution. We show that some clusters, namely pantocin B, PNP-3, and PNP-4 are found strictly in Pantoea, while agglomerin, andrimid, AGA, dapdiamide, herbicolin, PNP-1, PNP-2, PNP-5, and pantocin A, are more broadly distributed in distantly related genera within Vibrionaceae, Pectobacteriaceae, Yersiniaceae, Morganellaceae, and Hafniaceae. We evaluated the evolutionary history of these gene clusters relative to a cpn60-based species tree, considering the flanking regions of each cluster, %GC, and presence of mobile genetic elements, and identified potential occurrences of horizontal gene transfer. Lastly, we also describe the biosynthetic gene cluster of pantocin B in the strain Pantoea agglomerans Eh318 more than 20 years after this antibiotic was first described.
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7
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Andler O, Kazmaier U. Synthesis and biological evaluation of moiramide B derivatives. Org Biomol Chem 2024; 22:5284-5288. [PMID: 38864222 DOI: 10.1039/d4ob00856a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2024]
Abstract
Moiramide B is a peptide-polyketide hybrid with a bacterial origin and interesting antibiotic activity. Besides its structurally conserved peptide part, it contains a highly variable fatty acid side chain. We modified this part of the molecule by introducing a terminal alkyne, and we then subjected it to click reactions and Sonogashira couplings. This provided a library of moiramide B derivatives with high and selective in vivo activities against S. aureus.
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Affiliation(s)
- Oliver Andler
- Organic Chemistry, Saarland University, P.O. Box 151150, 66041 Saarbrücken, Germany.
| | - Uli Kazmaier
- Organic Chemistry, Saarland University, P.O. Box 151150, 66041 Saarbrücken, Germany.
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8
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Zhao L, Ge T, Cheng T, Wang Q, Cui M, Yuan H, Zhao L. Fine-tuning gene expression of regulator AdmX for improved biosynthesis of andrimid in Erwinia persicina BST187. Appl Microbiol Biotechnol 2023; 107:6775-6788. [PMID: 37715803 DOI: 10.1007/s00253-023-12770-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 08/17/2023] [Accepted: 09/01/2023] [Indexed: 09/18/2023]
Abstract
Andrimid is a potent antibiotic that inhibits acetyl-CoA carboxylase. However, its low biological yield and complex chemical synthesis have hindered its large-scale application. In this study, we found that the LysR-type transcriptional activator AdmX controls andrimid yield by adjusting its expression level in the andrimid-producing bacterium Erwinia persicina strain BST187. Our results showed that gradually increasing of admX transcriptional levels significantly improved andrimid yield, while the yield declined when admX was overexpressed excessively. To further estimate the effect of AdmX on andrimid promotion, we fitted and developed a model which was y = -0.5576x2 + 61.945x + 800.63 (R2 = 0.9591), where x represents the admX transcriptional level and y represents andrimid yield. Andrimid yield of admX overexpression strain BST187ΔadmX/pET28a-Pgap-1::admX was greatly improved by 260%, which was reported for the first time that andrimid yield could be promoted by genetic engineering. Thus, this study provides important insights that the biosynthesis of andrimid would be improved by bioengineering and sheds lights on the potential application of andrimid in both biomedicine and bioagricultural manipulation with its large-scale production in the future. KEY POINTS: • Andrimid production can be greatly promoted by genetic engineering on non-model chassis. • The relationship between AdmX abundance and andrimid yield in Erwinia persicina strain BST187 might be parabolic. • Erwinia persicina BST187 combined with chassis modification enable the promising applications in andrimid industrialization.
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Affiliation(s)
- Lunqiang Zhao
- Key Laboratory of Engineering Biology for Low Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China
- College of Biological Sciences, China Agricultural University, Beijing, China
| | - Tongling Ge
- Key Laboratory of Engineering Biology for Low Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China
- National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Tingfeng Cheng
- Key Laboratory of Engineering Biology for Low Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China
| | - Qing Wang
- Key Laboratory of Engineering Biology for Low Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China
- National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Meijie Cui
- Key Laboratory of Engineering Biology for Low Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China
| | - Hongli Yuan
- College of Biological Sciences, China Agricultural University, Beijing, China
| | - Lei Zhao
- Key Laboratory of Engineering Biology for Low Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China.
- National Center of Technology Innovation for Synthetic Biology, Tianjin, China.
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9
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Cheng T, Ge T, Zhao L, Hou Y, Xia J, Zhao L. Improved production of andrimid in Erwinia persicina BST187 strain by fermentation optimization. BMC Microbiol 2023; 23:268. [PMID: 37749510 PMCID: PMC10519088 DOI: 10.1186/s12866-023-02946-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 07/14/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUND Andrimid is reported to be a novel kind of polyketide-nonribosomal peptide hybrid product (PK-NRPs) that inhibits fatty acid biosynthesis in bacteria. Considering its great potential in biomedicine and biofarming, intensive studies have been conducted to increase the production of andrimid to overcome the excessive costs of chemosynthesis. In screening for species with broad-spectrum antibacterial activity, we detected andrimid in the fermentation products of Erwinia persicina BST187. To increase andrimid production, the BST187 fermentation medium formulation and fermentation conditions were optimized by using systematic design of experiments (One-Factor-At-A-Time, Plackett-Burman design, Response Surface Methodology). RESULTS The results indicate that the actual andrimid production reached 140.3 ± 1.28 mg/L under the optimized conditions (trisodium citrate dihydrate-30 g/L, beef extract-17.1 g/L, MgCl2·6H2O-100 mM, inoculation amount-1%, initial pH-7.0, fermentation time-36 h, temperature-19.7℃), which is 20-fold greater than the initial condition without optimization (7.00 ± 0.40 mg/L), consistent with the improved antibacterial effect of the fermentation supernatant. CONCLUSIONS The present study provides valuable information for improving andrimid production via optimization of the fermentation process, which will be of great value in the future industrialization of andrimid production.
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Affiliation(s)
- Tingfeng Cheng
- Key Laboratory of Engineering Biology for Low-carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Tongling Ge
- Key Laboratory of Engineering Biology for Low-carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China
- National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Lunqiang Zhao
- Key Laboratory of Engineering Biology for Low-carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China
- College of Biological Sciences, China Agricultural University, Beijing, China
| | - Yuyong Hou
- Key Laboratory of Engineering Biology for Low-carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China
- National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Jianye Xia
- Key Laboratory of Engineering Biology for Low-carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China.
- National Center of Technology Innovation for Synthetic Biology, Tianjin, China.
| | - Lei Zhao
- Key Laboratory of Engineering Biology for Low-carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin, 300308, China.
- National Center of Technology Innovation for Synthetic Biology, Tianjin, China.
- College of Biological Sciences, China Agricultural University, Beijing, China.
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10
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Romero-González LE, Rojas-Vargas J, Muriel-Millán LF, Bustos-Martínez J, Bustamante VH, Pardo-López L. Genomic and phenotypic characterization of Pseudomonas sp. GOM7, a novel marine bacterial species with antimicrobial activity against multidrug-resistant Staphylococcus aureus. PLoS One 2023; 18:e0288504. [PMID: 37440509 DOI: 10.1371/journal.pone.0288504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Antimicrobial resistance (AMR) represents a serious threat to global health. The development of new drugs to combat infections caused by bacteria resistant to multiple or even all available antibiotics is urgent. Most antibiotics used up to date have been identified from soil microorganisms. The marine environment represents an alternative source with great potential for the identification of microorganisms that produce bioactive molecules, including antibiotics. In this study, we analyzed the antibacterial activity of a collection of 82 bacterial strains isolated from marine water and sediment samples collected from the Southwestern Gulf of Mexico. Eight of the marine isolates inhibited the growth of different pathogenic bacteria, seven of which were identified as presumptive Pseudomonas aeruginosa. Interestingly, genome sequencing and phylogenetic analysis revealed that the remaining marine isolate showing antibacterial activity is a novel Pseudomonas species that we denominated Pseudomonas sp. GOM7, which was not pathogenic in the Galleria mellonella infection model in the conditions tested. Notably, Pseudomonas sp. GOM7 inhibited the growth of multidrug and methicillin-resistant strains of the priority pathogen Staphylococcus aureus. Our results show that the anti-S. aureus compound(s) produced by Pseudomonas sp. GOM7 can be extracted from the culture supernatant of this bacterium with the organic solvent ethyl acetate. Annotation of the Pseudomonas sp. GOM7 genome revealed the presence of several biosynthetic gene clusters predicted to code for possible antimicrobial compounds. Our results further highlight the potential of bacteria from the Gulf of Mexico as a source of novel antimicrobials.
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Affiliation(s)
- Luis E Romero-González
- Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México
| | - Jorge Rojas-Vargas
- Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México
| | - Luis F Muriel-Millán
- Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México
| | - Jaime Bustos-Martínez
- Departamento de Atención a la Salud, Universidad Autónoma Metropolitana Unidad Xochimilco, CDMX, México
| | - Víctor H Bustamante
- Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México
| | - Liliana Pardo-López
- Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México
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11
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Devkar HU, Thakur NL, Kaur P. Marine-derived antimicrobial molecules from the sponges and their associated bacteria. Can J Microbiol 2023; 69:1-16. [PMID: 36288610 DOI: 10.1139/cjm-2022-0147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Antimicrobial resistance (AMR) is one of the leading global health issues that demand urgent attention. Very soon the world will have to bear the consequences of increased drug resistance if new anti-infectives are not pumped into the clinical pipeline in a short period. This presses on the need for novel chemical entities, and the marine environment is one such hotspot to look for. The Ocean harbours a variety of organisms, of which from this aspect, "Sponges (Phylum Porifera)" are of particular interest. To tackle the stresses faced due to their sessile and filter-feeding lifestyle, sponges produce various bioactive compounds, which can be tapped for human use. The sponges harbour several microorganisms of different types and in most cases; the microbial symbionts are the actual producers of the bioactive compounds. This review describes the alarming need for the development of new antimicrobials and how marine sponges can contribute to this. Selected antimicrobial compounds from the marine sponges and their associated bacteria have been described. Additionally, measures to tackle the supply problem have been covered, which is the primary obstacle in marine natural product drug discovery.
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Affiliation(s)
- Heena U Devkar
- CSIR- National Institute of Oceanography, Dona Paula 403004, Goa, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Narsinh L Thakur
- CSIR- National Institute of Oceanography, Dona Paula 403004, Goa, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Parvinder Kaur
- Foundation for Neglected Disease Research, Bangalore 561203, Karnataka, India
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12
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Wang F, Zhang Z, Chen Y, Ratovelomanana-Vidal V, Yu P, Chen GQ, Zhang X. Stereodivergent synthesis of chiral succinimides via Rh-catalyzed asymmetric transfer hydrogenation. Nat Commun 2022; 13:7794. [PMID: 36528669 PMCID: PMC9759521 DOI: 10.1038/s41467-022-35124-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 11/18/2022] [Indexed: 12/23/2022] Open
Abstract
Chiral succinimide moieties are ubiquitous in biologically active natural products and pharmaceuticals. Until today, despite the great interest, little success has been made for stereodivergent synthesis of chiral succinimides. Here, we report a general and efficient method for accessing 3,4-disubstituted succinimides through a dynamic kinetic resolution strategy based on asymmetric transfer hydrogenation. The Rh catalyst system exhibit high activities, enantioselectivities, and diastereoselectivities (up to 2000 TON, up to >99% ee, and up to >99:1 dr). Products with syn- and anti-configuration are obtained separately by control of the reaction conditions. For the N-unprotected substrates, both the enol and the imide group can be reduced by control of reaction time and catalyst loading. In addition, the detailed reaction pathway and origin of stereoselectivity are elucidated by control experiments and theoretical calculations. This study offers a straightforward and stereodivergent approach to the valuable enantioenriched succinimides (all 4 stereoisomers) from cheap chemical feedstocks in a single reaction step.
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Affiliation(s)
- Fangyuan Wang
- grid.263817.90000 0004 1773 1790Department of Chemistry, Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, 518000 China
| | - Zongpeng Zhang
- grid.263817.90000 0004 1773 1790Department of Chemistry, Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, 518000 China
| | - Yu Chen
- grid.263817.90000 0004 1773 1790Department of Chemistry, Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, 518000 China
| | - Virginie Ratovelomanana-Vidal
- grid.4444.00000 0001 2112 9282PSL University, Chimie ParisTech, CNRS, Institute1 of Chemistry for Life and Health Sciences, CSB2D team, 75005 Paris, France
| | - Peiyuan Yu
- grid.263817.90000 0004 1773 1790Department of Chemistry, Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, 518000 China
| | - Gen-Qiang Chen
- grid.263817.90000 0004 1773 1790Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, 518000 China
| | - Xumu Zhang
- grid.263817.90000 0004 1773 1790Department of Chemistry, Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, 518000 China
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13
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Vastakaite G, Grünenfelder CE, Wennemers H. Peptide-Catalyzed Stereoselective Conjugate Addition Reaction of Aldehydes to C-Substituted Maleimides. Chemistry 2022; 28:e202200215. [PMID: 35089626 PMCID: PMC9306895 DOI: 10.1002/chem.202200215] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Indexed: 11/11/2022]
Abstract
Catalytic stereoselective additions with maleimides are useful one-step reactions to yield chiral succinimides, molecules that are widespread among therapeutically active compounds but challenging to prepare when the maleimide is C-substituted. We present the tripeptide H-Pro-Pro-Asp-NHC12 H25 as a catalyst for conjugate addition reactions between aldehydes and C-substituted maleimides to form succinimides with three contiguous stereogenic centers in high yields and stereoselectivities. The peptidic catalyst is so chemoselective that no protecting group is needed at the imide nitrogen of the maleimides. Derivatization of the succinimides was straightforward and provided access to chiral pyrrolidines, lactones, and lactams. Kinetic studies, including a Hammett plot, provided detailed insight into the reaction mechanism.
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Affiliation(s)
- Greta Vastakaite
- Laboratory of Organic ChemistryETH ZürichVladimir-Prelog-Weg 38093ZürichSwitzerland
| | | | - Helma Wennemers
- Laboratory of Organic ChemistryETH ZürichVladimir-Prelog-Weg 38093ZürichSwitzerland
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14
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Deutsch JM, Mandelare-Ruiz P, Yang Y, Foster G, Routhu A, Houk J, De La Flor YT, Ushijima B, Meyer JL, Paul VJ, Garg N. Metabolomics Approaches to Dereplicate Natural Products from Coral-Derived Bioactive Bacteria. JOURNAL OF NATURAL PRODUCTS 2022; 85:462-478. [PMID: 35112871 DOI: 10.1021/acs.jnatprod.1c01110] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Stony corals (Scleractinia) are invertebrates that form symbiotic relationships with eukaryotic algal endosymbionts and the prokaryotic microbiome. The microbiome has the potential to produce bioactive natural products providing defense and resilience to the coral host against pathogenic microorganisms, but this potential has not been extensively explored. Bacterial pathogens can pose a significant threat to corals, with some species implicated in primary and opportunistic infections of various corals. In response, probiotics have been proposed as a potential strategy to protect corals in the face of increased incidence of disease outbreaks. In this study, we screened bacterial isolates from healthy and diseased corals for antibacterial activity. The bioactive extracts were analyzed using untargeted metabolomics. Herein, an UpSet plot and hierarchical clustering analyses were performed to identify isolates with the largest number of unique metabolites. These isolates also displayed different antibacterial activities. Through application of in silico and experimental approaches coupled with genome analysis, we dereplicated natural products from these coral-derived bacteria from Florida's coral reef environments. The metabolomics approach highlighted in this study serves as a useful resource to select probiotic candidates and enables insights into natural product-mediated chemical ecology in holobiont symbiosis.
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Affiliation(s)
- Jessica M Deutsch
- School of Chemistry and Biochemistry, Engineered Biosystems Building, Center for Microbial Dynamics and Infection, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Paige Mandelare-Ruiz
- Smithsonian Marine Station, Smithsonian Institution, Fort Pierce, Florida 34949, United States
| | - Yingzhe Yang
- School of Chemistry and Biochemistry, Engineered Biosystems Building, Center for Microbial Dynamics and Infection, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Gabriel Foster
- School of Chemistry and Biochemistry, Engineered Biosystems Building, Center for Microbial Dynamics and Infection, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Apurva Routhu
- School of Chemistry and Biochemistry, Engineered Biosystems Building, Center for Microbial Dynamics and Infection, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Jay Houk
- Smithsonian Marine Station, Smithsonian Institution, Fort Pierce, Florida 34949, United States
| | - Yesmarie T De La Flor
- Smithsonian Marine Station, Smithsonian Institution, Fort Pierce, Florida 34949, United States
| | - Blake Ushijima
- Smithsonian Marine Station, Smithsonian Institution, Fort Pierce, Florida 34949, United States
- Department of Biology and Marine Biology, University of North Carolina Wilmington, Wilmington, North Carolina 28403, United States
| | - Julie L Meyer
- Department of Soil and Water Sciences, University of Florida, Gainesville, Florida 32603, United States
| | - Valerie J Paul
- Smithsonian Marine Station, Smithsonian Institution, Fort Pierce, Florida 34949, United States
| | - Neha Garg
- School of Chemistry and Biochemistry, Engineered Biosystems Building, Center for Microbial Dynamics and Infection, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
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15
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Wongso H. Natural product-based Radiopharmaceuticals:Focus on curcumin and its analogs, flavonoids, and marine peptides. J Pharm Anal 2021; 12:380-393. [PMID: 35811617 PMCID: PMC9257450 DOI: 10.1016/j.jpha.2021.07.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 05/19/2021] [Accepted: 07/19/2021] [Indexed: 02/07/2023] Open
Abstract
Natural products provide a bountiful supply of pharmacologically relevant precursors for the development of various drug-related molecules, including radiopharmaceuticals. However, current knowledge regarding the importance of natural products in developing new radiopharmaceuticals remains limited. To date, several radionuclides, including gallium-68, technetium-99m, fluorine-18, iodine-131, and iodine-125, have been extensively studied for the synthesis of diagnostic and therapeutic radiopharmaceuticals. The availability of various radiolabeling methods allows the incorporation of these radionuclides into bioactive molecules in a practical and efficient manner. Of the radiolabeling methods, direct radioiodination, radiometal complexation, and halogenation are generally suitable for natural products owing to their simplicity and robustness. This review highlights the pharmacological benefits of curcumin and its analogs, flavonoids, and marine peptides in treating human pathologies and provides a perspective on the potential use of these bioactive compounds as molecular templates for the design and development of new radiopharmaceuticals. Additionally, this review provides insights into the current strategies for labeling natural products with various radionuclides using either direct or indirect methods.
Potential use of natural products for the development of diagnostic and therapeutic radiopharmaceuticals. Profile of potential natural products as molecular templates for the synthesis of new radiopharmaceuticals: Focus on curcumin and its closely related substances, flavonoids, and marine peptides. Radiolabeling strategies, challenges, and examples of natural product-based radiopharmaceuticals under investigation.
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16
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Nguyen HT, Kim HG, Yu NH, Hwang IM, Kim H, Kim YC, Kim JC. In Vitro and In Vivo Antibacterial Activity of Serratamid, a Novel Peptide-Polyketide Antibiotic Isolated from Serratia plymuthica C1, against Phytopathogenic Bacteria. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:5471-5480. [PMID: 33914513 DOI: 10.1021/acs.jafc.1c01162] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
A new hybrid non-ribosomal peptide-polyketide antibiotic (serratamid) for phytoprotection was isolated from the ethyl acetate layer of tryptic soy agar culture of the soil bacterium Serratia plymuthica C1 through bioassay-guided fractionation. Its chemical structure was elucidated using instrumental analyses, such as mass and nuclear magnetic resonance spectrometry. Serratamid showed antibacterial activity against 15 phytopathogenic bacteria, with minimum inhibitory concentration (MIC) values ranging from 0.244 to 31.25 μg/mL. In vitro, it displayed strong antibacterial activity against Ralstonia solanacearum and four Xanthomonas spp., with MIC values (0.244-0.488 μg/mL) superior to those of streptomycin sulfate, oxolinic acid, and oxytetracycline. Further, serratamid and the ethyl acetate layer of S. plymuthica C1 effectively reduced bacterial wilt caused by R. solanacearum on tomato seedlings and fire blight caused by Erwinia on apple fruits in a dose-dependent manner. These results suggest that serratamid is a promising candidate as a potent bactericide for controlling bacterial diseases.
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Affiliation(s)
- Hoa Thi Nguyen
- Department of Agricultural Chemistry, Institute of Environmentally Friendly Agriculture, College of Agriculture and Life Sciences, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Hyoung-Geun Kim
- Natural Product Chemistry Lab, Graduate School of Biotechnology, Kyung Hee University, Yongin, Gyeonggi 17104, Republic of Korea
| | - Nan Hee Yu
- Department of Agricultural Chemistry, Institute of Environmentally Friendly Agriculture, College of Agriculture and Life Sciences, Chonnam National University, Gwangju 61186, Republic of Korea
| | - In Min Hwang
- Hygienic Safety and Analysis Center, World Institute of Kimchi, Gwangju 61755, Republic of Korea
| | - Hun Kim
- Center for Eco-friendly New Materials, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
| | - Young Cheol Kim
- Department of Applied Biology, College of Agriculture and Life Sciences, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Jin-Cheol Kim
- Department of Agricultural Chemistry, Institute of Environmentally Friendly Agriculture, College of Agriculture and Life Sciences, Chonnam National University, Gwangju 61186, Republic of Korea
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17
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Zhao Z, Yue J, Ji X, Nian M, Kang K, Qiao H, Zheng X. Research progress in biological activities of succinimide derivatives. Bioorg Chem 2020; 108:104557. [PMID: 33376010 DOI: 10.1016/j.bioorg.2020.104557] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/03/2020] [Accepted: 12/10/2020] [Indexed: 12/11/2022]
Abstract
Succinimides are well recognized heterocyclic compounds in drug discovery which produce diverse therapeutically related applications in pharmacological practices. Researches in medicinal chemistry field have isolated and synthesized succinimide derivatives with multiple medicinal properties including anticonvulsant, anti-inflammatory, antitumor and antimicrobial agents, 5-HT receptor ligands and enzyme inhibitors. Simultaneously, SAR (Structure-Activity Relationship) analysis has been gradually possessed, along with a great deal of derivatives have been derived for potential targets. In this article, we comprehensively summarize the biological activities and SAR for succinimide derivatives, along with the featuring bioactive molecules reported in patents, wishing to provide an overall retrospect and prospect on the succinimide analogues.
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Affiliation(s)
- Zefeng Zhao
- College of Acupuncture & Massage, Shaanxi University of Chinese Medicine, Xixian New Area, Shaanxi Province 712046, PR China; Shaanxi Key Laboratory of Acupuncture & Medicine, Xixian New Area, Shaanxi Province 712046, PR China; School of Pharmacy, Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Biomedicine Key Laboratory of Shaanxi Province, Northwest University, 229 Taibai Road, Xi'an 710069, PR China
| | - Jiangxin Yue
- Shaanxi Key Laboratory of Acupuncture & Medicine, Xixian New Area, Shaanxi Province 712046, PR China
| | - Xiaotong Ji
- Shaanxi Key Laboratory of Acupuncture & Medicine, Xixian New Area, Shaanxi Province 712046, PR China
| | - Meng Nian
- Shaanxi Key Laboratory of Acupuncture & Medicine, Xixian New Area, Shaanxi Province 712046, PR China
| | - Kaiwen Kang
- Shaanxi Key Laboratory of Acupuncture & Medicine, Xixian New Area, Shaanxi Province 712046, PR China
| | - Haifa Qiao
- College of Acupuncture & Massage, Shaanxi University of Chinese Medicine, Xixian New Area, Shaanxi Province 712046, PR China; Shaanxi Key Laboratory of Acupuncture & Medicine, Xixian New Area, Shaanxi Province 712046, PR China.
| | - Xiaohui Zheng
- School of Pharmacy, Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Biomedicine Key Laboratory of Shaanxi Province, Northwest University, 229 Taibai Road, Xi'an 710069, PR China
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18
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Williams AN, Sorout N, Cameron AJ, Stavrinides J. The Integration of Genome Mining, Comparative Genomics, and Functional Genetics for Biosynthetic Gene Cluster Identification. Front Genet 2020; 11:600116. [PMID: 33343637 PMCID: PMC7744662 DOI: 10.3389/fgene.2020.600116] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/11/2020] [Indexed: 11/25/2022] Open
Abstract
Antimicrobial resistance is a worldwide health crisis for which new antibiotics are needed. One strategy for antibiotic discovery is identifying unique antibiotic biosynthetic gene clusters that may produce novel compounds. The aim of this study was to demonstrate how an integrated approach that combines genome mining, comparative genomics, and functional genetics can be used to successfully identify novel biosynthetic gene clusters that produce antimicrobial natural products. Secondary metabolite clusters of an antibiotic producer are first predicted using genome mining tools, generating a list of candidates. Comparative genomic approaches are then used to identify gene suites present in the antibiotic producer that are absent in closely related non-producers. Gene sets that are common to the two lists represent leading candidates, which can then be confirmed using functional genetics approaches. To validate this strategy, we identified the genes responsible for antibiotic production in Pantoea agglomerans B025670, a strain identified in a large-scale bioactivity survey. The genome of B025670 was first mined with antiSMASH, which identified 24 candidate regions. We then used the comparative genomics platform, EDGAR, to identify genes unique to B025670 that were not present in closely related strains with contrasting antibiotic production profiles. The candidate lists generated by antiSMASH and EDGAR were compared with standalone BLAST. Among the common regions was a 14 kb cluster consisting of 14 genes with predicted enzymatic, transport, and unknown functions. Site-directed mutagenesis of the gene cluster resulted in a reduction in antimicrobial activity, suggesting involvement in antibiotic production. An integrated approach that combines genome mining, comparative genomics, and functional genetics yields a powerful, yet simple strategy for identifying potentially novel antibiotics.
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19
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Barbosa F, Pinto E, Kijjoa A, Pinto M, Sousa E. Targeting antimicrobial drug resistance with marine natural products. Int J Antimicrob Agents 2020; 56:106005. [PMID: 32387480 DOI: 10.1016/j.ijantimicag.2020.106005] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 01/10/2023]
Abstract
The rise and spread of antimicrobial resistance represents one of the most pressing health issues of today. Antimicrobial resistance in micro-organisms can arise due to a multiplicity of factors, including permeability changes in the cell membrane, increase of drug efflux pumps, enzymatic modification or inactivation of the antibiotic, target site modification, alternative metabolic pathways and biofilm formation. The marine environment is a valuable source of diverse natural products with a huge variety of biological activities. Among them, antimicrobial compounds show promising biological activities against numerous drug-resistant bacteria and fungi, making marine natural products a very promising resource in the search for novel antimicrobial agents. This review summarises the state-of-art of marine natural products with antibacterial and antifungal properties against drug-resistant micro-organisms. These natural products were categorised based on their chemical structure, and their respective sources and activities are highlighted. The chemical diversity associated with these marine-derived molecules is enormous, including peptides, polyketides, alkaloids, sterols, terpenoids, lactones, halogenated compounds, nucleosides, etc., some of which have rare substructures. Some of the marine compounds mentioned do not have intrinsic antimicrobial activity but potentiate the antimicrobial effect of other antimicrobials via inhibition of efflux pumps. Although these agents are still in preclinical studies, evidence of their in vivo efficacy suggest research of new drugs from the ocean to overcome antimicrobial resistance in order to fulfil an unmet medical need.
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Affiliation(s)
- Filipa Barbosa
- Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Eugénia Pinto
- Laboratory of Microbiology, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; CIIMAR/CIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, 4450-208 Matosinhos, Portugal
| | - Anake Kijjoa
- CIIMAR/CIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, 4450-208 Matosinhos, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Madalena Pinto
- Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; CIIMAR/CIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, 4450-208 Matosinhos, Portugal
| | - Emília Sousa
- Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; CIIMAR/CIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, 4450-208 Matosinhos, Portugal.
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20
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The Biological and Chemical Diversity of Tetramic Acid Compounds from Marine-Derived Microorganisms. Mar Drugs 2020; 18:md18020114. [PMID: 32075282 PMCID: PMC7074263 DOI: 10.3390/md18020114] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/12/2020] [Accepted: 02/14/2020] [Indexed: 12/25/2022] Open
Abstract
Tetramic acid (pyrrolidine-2,4-dione) compounds, isolated from a variety of marine and terrestrial organisms, have attracted considerable attention for their diverse, challenging structural complexity and promising bioactivities. In the past decade, marine-derived microorganisms have become great repositories of novel tetramic acids. Here, we discuss the biological activities of 277 tetramic acids of eight classifications (simple 3-acyl tetramic acids, 3-oligoenoyltetramic acids, 3-decalinoyltetramic acid, 3-spirotetramic acids, macrocyclic tetramic acids, N-acylated tetramic acids, α-cyclopiazonic acid-type tetramic acids, and other tetramic acids) from marine-derived microbes, including fungi, actinobacteria, bacteria, and cyanobacteria, as reported in 195 research studies up to 2019.
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21
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Chortani S, Nimbarte VD, Horchani M, Ben Jannet H, Romdhane A. Synthesis, biological evaluation and molecular docking analysis of novel benzopyrimidinone derivatives as potential anti-tyrosinase agents. Bioorg Chem 2019; 92:103270. [DOI: 10.1016/j.bioorg.2019.103270] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 08/13/2019] [Accepted: 09/09/2019] [Indexed: 10/26/2022]
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22
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Tian S, Song X, Zhu D, Wang M. Alternative Palladium-Catalyzed Vinylic C−H Difluoroalkylation of Ketene Dithioacetals Using Bromodifluoroacetate Derivatives. Adv Synth Catal 2018. [DOI: 10.1002/adsc.201701554] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Shuangquan Tian
- Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, College of Chemistry; Northeast Normal University; Renmin Street 5268 Changchun 130024 People's Republic of China
| | - Xiaoning Song
- Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, College of Chemistry; Northeast Normal University; Renmin Street 5268 Changchun 130024 People's Republic of China
| | - Dongsheng Zhu
- Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, College of Chemistry; Northeast Normal University; Renmin Street 5268 Changchun 130024 People's Republic of China
| | - Mang Wang
- Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, College of Chemistry; Northeast Normal University; Renmin Street 5268 Changchun 130024 People's Republic of China
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23
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Timmermans ML, Paudel YP, Ross AC. Investigating the Biosynthesis of Natural Products from Marine Proteobacteria: A Survey of Molecules and Strategies. Mar Drugs 2017; 15:E235. [PMID: 28762997 PMCID: PMC5577590 DOI: 10.3390/md15080235] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Revised: 07/21/2017] [Accepted: 07/24/2017] [Indexed: 02/07/2023] Open
Abstract
The phylum proteobacteria contains a wide array of Gram-negative marine bacteria. With recent advances in genomic sequencing, genome analysis, and analytical chemistry techniques, a whole host of information is being revealed about the primary and secondary metabolism of marine proteobacteria. This has led to the discovery of a growing number of medically relevant natural products, including novel leads for the treatment of multidrug-resistant Staphylococcus aureus (MRSA) and cancer. Of equal interest, marine proteobacteria produce natural products whose structure and biosynthetic mechanisms differ from those of their terrestrial and actinobacterial counterparts. Notable features of secondary metabolites produced by marine proteobacteria include halogenation, sulfur-containing heterocycles, non-ribosomal peptides, and polyketides with unusual biosynthetic logic. As advances are made in the technology associated with functional genomics, such as computational sequence analysis, targeted DNA manipulation, and heterologous expression, it has become easier to probe the mechanisms for natural product biosynthesis. This review will focus on genomics driven approaches to understanding the biosynthetic mechanisms for natural products produced by marine proteobacteria.
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Affiliation(s)
| | - Yagya P Paudel
- Department of Chemistry, Queen's University, Kingston, ON K7L 3N6, Canada.
| | - Avena C Ross
- Department of Chemistry, Queen's University, Kingston, ON K7L 3N6, Canada.
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24
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Masschelein J, Jenner M, Challis GL. Antibiotics from Gram-negative bacteria: a comprehensive overview and selected biosynthetic highlights. Nat Prod Rep 2017. [PMID: 28650032 DOI: 10.1039/c7np00010c] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Covering: up to 2017The overwhelming majority of antibiotics in clinical use originate from Gram-positive Actinobacteria. In recent years, however, Gram-negative bacteria have become increasingly recognised as a rich yet underexplored source of novel antimicrobials, with the potential to combat the looming health threat posed by antibiotic resistance. In this article, we have compiled a comprehensive list of natural products with antimicrobial activity from Gram-negative bacteria, including information on their biosynthetic origin(s) and molecular target(s), where known. We also provide a detailed discussion of several unusual pathways for antibiotic biosynthesis in Gram-negative bacteria, serving to highlight the exceptional biocatalytic repertoire of this group of microorganisms.
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Affiliation(s)
- J Masschelein
- Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, UK.
| | - M Jenner
- Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, UK.
| | - G L Challis
- Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, UK.
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25
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Mamo G. Anaerobes as Sources of Bioactive Compounds and Health Promoting Tools. ADVANCES IN BIOCHEMICAL ENGINEERING/BIOTECHNOLOGY 2017; 156:433-464. [PMID: 27432247 DOI: 10.1007/10_2016_6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Aerobic microorganisms have been sources of medicinal agents for several decades and an impressive variety of drugs have been isolated from their cultures, studied and formulated to treat or prevent diseases. On the other hand, anaerobes, which are believed to be the oldest life forms on earth and evolved remarkably diverse physiological functions, have largely been neglected as sources of bioactive compounds. However, results obtained from the limited research done so far show that anaerobes are capable of producing a range of interesting bioactive compounds that can promote human health. In fact, some of these bioactive compounds are found to be novel in their structure and/or mode of action.Anaerobes play health-promoting roles through their bioactive products as well as application of whole cells. The bioactive compounds produced by these microorganisms include antimicrobial agents and substances such as immunomodulators and vitamins. Bacteriocins produced by anaerobes have been in use as preservatives for about 40 years. Because these substances are effective at low concentrations, encounter relatively less resistance from bacteria and are safe to use, there is a growing interest in these antimicrobial agents. Moreover, several antibiotics have been reported from the cultures of anaerobes. Closthioamide and andrimid produced by Clostridium cellulolyticum and Pantoea agglomerans, respectively, are examples of novel antibiotics of anaerobe origin. The discovery of such novel bioactive compounds is expected to encourage further studies which can potentially lead to tapping of the antibiotic production potential of this fascinating group of microorganisms.Anaerobes are widely used in preparation of fermented foods and beverages. During the fermentation processes, these organisms produce a number of bioactive compounds including anticancer, antihypertensive and antioxidant substances. The well-known health promoting effect of fermented food is mostly due to these bioactive compounds. In addition to their products, whole cell anaerobes have very interesting applications for enhancing the quality of life. Probiotic anaerobes have been on the market for many years and are receiving growing acceptance as health promoters. Gut anaerobes have been used to treat patients suffering from severe Clostridium difficile infection syndromes including diarrhoea and colitis which cannot be treated by other means. Whole cell anaerobes are also studied to detect and cure cancer. In recent years, evidence is emerging that anaerobes constituting the microbiome are linked to our overall health. A dysfunctional microbiome is believed to be the cause of many diseases including cancer, allergy, infection, obesity, diabetes and several other disorders. Maintaining normal microflora is believed to alleviate some of these serious health problems. Indeed, the use of probiotics and prebiotics which favourably change the number and composition of the gut microflora is known to render a health promoting effect. Our interaction with the microbiome anaerobes is complex. In fact, not only our lives but also our identities are more closely linked to the anaerobic microbial world than we may possibly imagine. We are just at the beginning of unravelling the secret of association between the microbiome and human body, and a clear understanding of the association may bring a paradigm shift in the way we diagnose and treat diseases and disorders. This chapter highlights some of the work done on bioactive compounds and whole cell applications of the anaerobes that foster human health and improve the quality of life.
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Affiliation(s)
- Gashaw Mamo
- Biotechnology, Center for Chemistry & Chemical Engineering, Lund University, 221 00, Lund, Sweden.
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Growth on Chitin Impacts the Transcriptome and Metabolite Profiles of Antibiotic-Producing Vibrio coralliilyticus S2052 and Photobacterium galatheae S2753. mSystems 2017; 2:mSystems00141-16. [PMID: 28066819 PMCID: PMC5209532 DOI: 10.1128/msystems.00141-16] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 11/30/2016] [Indexed: 11/20/2022] Open
Abstract
The bacterial family Vibrionaceae (vibrios) is considered a major player in the degradation of chitin, the most abundant polymer in the marine environment; however, the majority of studies on the topic have focused on a small number of Vibrio species. In this study, we analyzed the genomes of two vibrios to assess their genetic potential for the degradation of chitin. We then used transcriptomics and metabolomics to demonstrate that chitin strongly affects these vibrios at both the transcriptional and metabolic levels. We observed a strong increase in production of secondary metabolites, suggesting an ecological role for these molecules during chitin colonization in the marine environment. Members of the Vibrionaceae family are often associated with chitin-containing organisms, and they are thought to play a major role in chitin degradation. The purpose of the present study was to determine how chitin affects the transcriptome and metabolome of two bioactive Vibrionaceae strains, Vibrio coralliilyticus and Photobacterium galatheae. We focused on chitin degradation genes and secondary metabolites based on the assumption that these molecules in nature confer an advantage to the producer. Growth on chitin caused upregulation of genes related to chitin metabolism and of genes potentially involved in host colonization and/or infection. The expression of genes involved in secondary metabolism was also significantly affected by growth on chitin, in one case being 34-fold upregulated. This was reflected in the metabolome, where the antibiotics andrimid and holomycin were produced in larger amounts on chitin. Other polyketide synthase/ nonribosomal peptide synthetase (PKS-NRPS) clusters in P. galatheae were also strongly upregulated on chitin. Collectively, this suggests that both V. coralliilyticus and P. galatheae have a specific lifestyle for growth on chitin and that their secondary metabolites likely play a crucial role during chitin colonization. IMPORTANCE The bacterial family Vibrionaceae (vibrios) is considered a major player in the degradation of chitin, the most abundant polymer in the marine environment; however, the majority of studies on the topic have focused on a small number of Vibrio species. In this study, we analyzed the genomes of two vibrios to assess their genetic potential for the degradation of chitin. We then used transcriptomics and metabolomics to demonstrate that chitin strongly affects these vibrios at both the transcriptional and metabolic levels. We observed a strong increase in production of secondary metabolites, suggesting an ecological role for these molecules during chitin colonization in the marine environment.
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Bozdoğan B, Erşatır M, Demirkol O, Akbaşlar D, Giray ES. Simple and efficient synthesis of N-alkyl and N-aryl succinimides in hot water. SYNTHETIC COMMUN 2016. [DOI: 10.1080/00397911.2016.1258479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Burcu Bozdoğan
- Department of Chemistry, Art & Science Faculty, Çukurova University, Adana, Turkey
| | - Mehmet Erşatır
- Department of Chemistry, Art & Science Faculty, Çukurova University, Adana, Turkey
| | - Onur Demirkol
- Department of Chemistry, Art & Science Faculty, Çukurova University, Adana, Turkey
| | - Dilek Akbaşlar
- Department of Chemistry, Art & Science Faculty, Çukurova University, Adana, Turkey
| | - E. Sultan Giray
- Department of Chemistry, Art & Science Faculty, Çukurova University, Adana, Turkey
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Matilla MA, Nogellova V, Morel B, Krell T, Salmond GPC. Biosynthesis of the acetyl-CoA carboxylase-inhibiting antibiotic, andrimid in Serratia is regulated by Hfq and the LysR-type transcriptional regulator, AdmX. Environ Microbiol 2016; 18:3635-3650. [PMID: 26914969 PMCID: PMC5216899 DOI: 10.1111/1462-2920.13241] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 01/20/2016] [Indexed: 12/30/2022]
Abstract
Infections due to multidrug-resistant bacteria represent a major global health challenge. To combat this problem, new antibiotics are urgently needed and some plant-associated bacteria are a promising source. The rhizobacterium Serratia plymuthica A153 produces several bioactive secondary metabolites, including the anti-oomycete and antifungal haterumalide, oocydin A and the broad spectrum polyamine antibiotic, zeamine. In this study, we show that A153 produces a second broad spectrum antibiotic, andrimid. Using genome sequencing, comparative genomics and mutagenesis, we defined new genes involved in andrimid (adm) biosynthesis. Both the expression of the adm gene cluster and regulation of andrimid synthesis were investigated. The biosynthetic cluster is operonic and its expression is modulated by various environmental cues, including temperature and carbon source. Analysis of the genome context of the adm operon revealed a gene encoding a predicted LysR-type regulator, AdmX, apparently unique to Serratia strains. Mutagenesis and gene expression assays demonstrated that AdmX is a transcriptional activator of the adm gene cluster. At the post-transcriptional level, the expression of the adm cluster is positively regulated by the RNA chaperone, Hfq, in an RpoS-independent manner. Our results highlight the complexity of andrimid biosynthesis - an antibiotic with potential clinical and agricultural utility.
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Affiliation(s)
- Miguel A. Matilla
- Department of BiochemistryUniversity of CambridgeTennis Court RoadCambridgeCB2 1QWUK
- Department of Environmental ProtectionEstación Experimental del Zaidín, Consejo Superior de Investigaciones CientíficasProf. Albareda 1Granada18008Spain
| | - Veronika Nogellova
- Department of BiochemistryUniversity of CambridgeTennis Court RoadCambridgeCB2 1QWUK
| | - Bertrand Morel
- Department of Environmental ProtectionEstación Experimental del Zaidín, Consejo Superior de Investigaciones CientíficasProf. Albareda 1Granada18008Spain
| | - Tino Krell
- Department of Environmental ProtectionEstación Experimental del Zaidín, Consejo Superior de Investigaciones CientíficasProf. Albareda 1Granada18008Spain
| | - George P. C. Salmond
- Department of BiochemistryUniversity of CambridgeTennis Court RoadCambridgeCB2 1QWUK
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Han Z, Li P, Zhang Z, Chen C, Wang Q, Dong XQ, Zhang X. Highly Enantioselective Synthesis of Chiral Succinimides via Rh/Bisphosphine-Thiourea-Catalyzed Asymmetric Hydrogenation. ACS Catal 2016. [DOI: 10.1021/acscatal.6b01615] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Zhengyu Han
- College
of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China
| | - Pan Li
- College
of Chemical Engineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, P.R. China
| | - Zongpeng Zhang
- College
of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China
| | - Caiyou Chen
- College
of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China
| | - Qian Wang
- College
of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China
| | - Xiu-Qin Dong
- College
of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China
| | - Xumu Zhang
- College
of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China
- Department
of Chemistry, South University of Science and Technology of China, Shenzhen, Guangdong 518055, P. R. China
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Silvers MA, Pakhomova S, Neau DB, Silvers WC, Anzalone N, Taylor CM, Waldrop GL. Crystal Structure of Carboxyltransferase from Staphylococcus aureus Bound to the Antibacterial Agent Moiramide B. Biochemistry 2016; 55:4666-74. [PMID: 27471863 DOI: 10.1021/acs.biochem.6b00641] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The dramatic increase in the prevalence of antibiotic-resistant bacteria has necessitated a search for new antibacterial agents against novel targets. Moiramide B is a natural product, broad-spectrum antibiotic that inhibits the carboxyltransferase component of acetyl-CoA carboxylase, which catalyzes the first committed step in fatty acid synthesis. Herein, we report the 2.6 Å resolution crystal structure of moiramide B bound to carboxyltransferase. An unanticipated but significant finding was that moiramide B bound as the enol/enolate. Crystallographic studies demonstrate that the (4S)-methyl succinimide moiety interacts with the oxyanion holes of the enzyme, supporting the notion that an anionic enolate is the active form of the antibacterial agent. Structure-activity studies demonstrate that the unsaturated fatty acid tail of moiramide B is needed only for entry into the bacterial cell. These results will allow the design of new antibacterial agents against the bacterial form of carboxyltransferase.
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Affiliation(s)
| | | | - David B Neau
- Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853-1301, United States.,Northeastern Collaborative Access Team, Argonne National Laboratory , Argonne, Illinois 60439, United States
| | - William C Silvers
- Department of Radiology, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States
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Hwang IH, Che Y, Swenson DC, Gloer JB, Wicklow DT, Peterson SW, Dowd PF. Haenamindole and fumiquinazoline analogs from a fungicolous isolate of Penicillium lanosum. J Antibiot (Tokyo) 2016; 69:631-6. [DOI: 10.1038/ja.2016.74] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 05/25/2016] [Accepted: 05/28/2016] [Indexed: 11/09/2022]
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Molleti N, Bjornberg C, Kang JY. Phospha-Michael addition reaction of maleimides employing N-heterocyclic phosphine-thiourea as a phosphonylation reagent: synthesis of 1-aryl-2,5-dioxopyrrolidine-3-yl-phosphonate derivatives. Org Biomol Chem 2016; 14:10695-10704. [DOI: 10.1039/c6ob01987k] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The phospha-Michael addition reaction of maleimides with NHP-thiourea under catalyst and additive free conditions has been developed for desymmetrization of maleimides.
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Affiliation(s)
- Nagaraju Molleti
- Department of Chemistry and Biochemistry
- University of Nevada Las Vegas
- Las Vegas
- USA
| | - Chad Bjornberg
- Department of Chemistry and Biochemistry
- University of Nevada Las Vegas
- Las Vegas
- USA
| | - Jun Yong Kang
- Department of Chemistry and Biochemistry
- University of Nevada Las Vegas
- Las Vegas
- USA
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Silvers MA, Robertson GT, Taylor CM, Waldrop GL. Design, Synthesis, and Antibacterial Properties of Dual-Ligand Inhibitors of Acetyl-CoA Carboxylase. J Med Chem 2014; 57:8947-59. [DOI: 10.1021/jm501082n] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Molly A. Silvers
- Division
of Biochemistry and Molecular Biology, Louisiana State University, Baton Rouge, Louisiana 70803, United States
| | - Gregory T. Robertson
- Department
of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Carol M. Taylor
- Department
of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States
| | - Grover L. Waldrop
- Division
of Biochemistry and Molecular Biology, Louisiana State University, Baton Rouge, Louisiana 70803, United States
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Fair RJ, Tor Y. Antibiotics and bacterial resistance in the 21st century. PERSPECTIVES IN MEDICINAL CHEMISTRY 2014; 6:25-64. [PMID: 25232278 PMCID: PMC4159373 DOI: 10.4137/pmc.s14459] [Citation(s) in RCA: 871] [Impact Index Per Article: 79.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 06/24/2014] [Accepted: 06/24/2014] [Indexed: 12/11/2022]
Abstract
Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed.
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Affiliation(s)
- Richard J Fair
- Department for Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Berlin, Germany
| | - Yitzhak Tor
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA
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Still PC, Johnson TA, Theodore CM, Loveridge ST, Crews P. Scrutinizing the scaffolds of marine biosynthetics from different source organisms: Gram-negative cultured bacterial products enter center stage. JOURNAL OF NATURAL PRODUCTS 2014; 77:690-702. [PMID: 24571234 PMCID: PMC4095796 DOI: 10.1021/np500041x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Compounds from macro marine organisms are presumed to owe their biosynthetic origins to associated microbial symbionts, although few definitive examples exist. An upsurge in the recent literature from 2012 to 2013 has shown that four compounds previously reported from macro marine organisms are in fact biosynthesized by non-photosynthetic Gram-negative bacteria (NPGNB). Structural parallels between compounds isolated from macro marine organisms and NPGNB producers form the basis of this review. Although less attention has been given to investigating the chemistry of NPGNB sources, there exists a significant list of structural parallels between NPGNB and macro marine organism-derived compounds. Alternatively, of the thousands of compounds isolated from Gram-positive actinomycetes, few structural parallels with macro marine organisms are known. A summary of small molecules isolated from marine NPGNB sources is presented, including compounds isolated from marine myxobacteria. From this assemblage of structural parallels and diverse chemical structures, it is hypothesized that the potential for the discovery of inspirational molecules from NPGNB sources is vast and that the recent spike in the literature of macro marine compounds owing their biosynthetic origin to NPGNB producers represents a turning point in the field.
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Affiliation(s)
- Patrick C. Still
- Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95060, United States
| | - Tyler A. Johnson
- Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95060, United States
| | - Christine M. Theodore
- Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95060, United States
| | - Steven T. Loveridge
- Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95060, United States
| | - Phillip Crews
- Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95060, United States
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Pidot SJ, Coyne S, Kloss F, Hertweck C. Antibiotics from neglected bacterial sources. Int J Med Microbiol 2014; 304:14-22. [DOI: 10.1016/j.ijmm.2013.08.011] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Marine bacteria: potential sources for compounds to overcome antibiotic resistance. Appl Microbiol Biotechnol 2013; 97:4763-73. [PMID: 23640363 DOI: 10.1007/s00253-013-4905-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Revised: 04/04/2013] [Accepted: 04/05/2013] [Indexed: 10/26/2022]
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is the most problematic Gram-positive bacterium in the context of public health due to its resistance against almost all available antibiotics except vancomycin and teicoplanin. Moreover, glycopeptide-resistant S. aureus have been emerging with the increasing use of glycopeptides. Recently, resistant strains against linezolid and daptomycin, which are alternative drugs to treat MRSA infection, have also been reported. Thus, the development of new drugs or alternative therapies is clearly a matter of urgency. In response to the antibiotic resistance, many researchers have studied for alternative antibiotics and therapies. In this review, anti-MRSA substances isolated from marine bacteria, with their potential antibacterial effect against MRSA as potential anti-MRSA agents, are discussed and several strategies for overcoming the antibiotic resistance are also introduced. Our objective was to highlight marine bacteria that have potential to lead in developing novel antibiotics or clinically useful alternative therapeutic treatments.
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Andrimid production at low temperature by a psychrotolerant Serratia proteamaculans strain. World J Microbiol Biotechnol 2013; 29:1773-81. [DOI: 10.1007/s11274-013-1338-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Accepted: 03/24/2013] [Indexed: 12/29/2022]
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A capillary electrophoretic assay for acetyl coenzyme A carboxylase. Anal Biochem 2013; 437:32-8. [PMID: 23435309 DOI: 10.1016/j.ab.2013.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 01/24/2013] [Accepted: 02/07/2013] [Indexed: 01/18/2023]
Abstract
A simple off-column capillary electrophoretic (CE) assay for measuring acetyl coenzyme A carboxylase holoenzyme (holo-ACC) activity and inhibition was developed. The two reactions catalyzed by the holo-ACC components, biotin carboxylase (BC) and carboxyltransferase (CT), were simultaneously monitored in this assay. Acetyl coenzyme A (CoA), malonyl-CoA, adenosine triphosphate (ATP), and adenosine diphosphate (ADP) were separated by capillary electrophoresis, and the depletion of ATP and acetyl-CoA as well as the production of ADP and malonyl-CoA were monitored. Inhibition of holo-ACC by the BC inhibitor, 2-amino-N,N-dibenzyloxazole-5-carboxamide, and the carboxyltransferase inhibitor, andrimid, was confirmed using this assay. A previously reported off-column CE assay for only the CT component of ACC was optimized, and an off-column CE assay for the BC component of ACC also was developed.
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Gómez-Torres E, Alonso DA, Gómez-Bengoa E, Nájera C. Enantioselective Synthesis of Succinimides by Michael Addition of 1,3-Dicarbonyl Compounds to Maleimides Catalyzed by a Chiral Bis(2-aminobenzimidazole) Organocatalyst. European J Org Chem 2012. [DOI: 10.1002/ejoc.201201046] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Mansson M, Nielsen A, Kjærulff L, Gotfredsen CH, Wietz M, Ingmer H, Gram L, Larsen TO. Inhibition of virulence gene expression in Staphylococcus aureus by novel depsipeptides from a marine photobacterium. Mar Drugs 2011; 9:2537-2552. [PMID: 22363239 PMCID: PMC3280567 DOI: 10.3390/md9122537] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Revised: 11/22/2011] [Accepted: 11/30/2011] [Indexed: 12/15/2022] Open
Abstract
During a global research expedition, more than five hundred marine bacterial strains capable of inhibiting the growth of pathogenic bacteria were collected. The purpose of the present study was to determine if these marine bacteria are also a source of compounds that interfere with the agr quorum sensing system that controls virulence gene expression in Staphylococcus aureus. Using a gene reporter fusion bioassay, we recorded agr interference as enhanced expression of spa, encoding Protein A, concomitantly with reduced expression of hla, encoding α-hemolysin, and rnaIII encoding RNAIII, the effector molecule of agr. A marine Photobacterium produced compounds interfering with agr in S. aureus strain 8325-4, and bioassay-guided fractionation of crude extracts led to the isolation of two novel cyclodepsipeptides, designated solonamide A and B. Northern blot analysis confirmed the agr interfering activity of pure solonamides in both S. aureus strain 8325-4 and the highly virulent, community-acquired strain USA300 (CA-MRSA). To our knowledge, this is the first report of inhibitors of the agr system by a marine bacterium.
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Affiliation(s)
- Maria Mansson
- Center for Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark;
- Author to whom correspondence should be addressed; ; Tel.: +45-4525-2724; Fax: +45-4588-4148
| | - Anita Nielsen
- Department of Veterinary Disease Biology, Faculty of Life Sciences, University of Copenhagen, DK-1870 Frederiksberg C, Denmark; (A.N.); (H.I.)
| | - Louise Kjærulff
- Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark; (L.K.); (C.H.G.)
| | - Charlotte H. Gotfredsen
- Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark; (L.K.); (C.H.G.)
| | - Matthias Wietz
- National Food Institute, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark; (M.W.); (L.G.)
| | - Hanne Ingmer
- Department of Veterinary Disease Biology, Faculty of Life Sciences, University of Copenhagen, DK-1870 Frederiksberg C, Denmark; (A.N.); (H.I.)
| | - Lone Gram
- National Food Institute, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark; (M.W.); (L.G.)
| | - Thomas O. Larsen
- Center for Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark;
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Wietz M, Månsson M, Gram L. Chitin stimulates production of the antibiotic andrimid in a Vibrio coralliilyticus strain. ENVIRONMENTAL MICROBIOLOGY REPORTS 2011; 3:559-564. [PMID: 23761335 DOI: 10.1111/j.1758-2229.2011.00259.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Vibrio coralliilyticus is a putative coral pathogen in tropical oceans, but also possesses antagonistic traits. We previously reported antibacterial activity in Vibrio coralliilyticus strain S2052 based upon the antibiotic andrimid. The purpose of the present study was to determine whether V. coralliilyticus S2052 produces the antibiotic under conditions mimicking natural habitats of vibrios. S2052 synthesized andrimid with both chitin and macroalgal extracts as sole nutrient source. With chitin, the biosynthesis of metabolites other than andrimid was largely abolished, and the yield of the antibiotic per cell was twofold higher. In cultures with Artemia as live chitin model system, S2052 reached up to 10(8) cells ml(-1) , produced andrimid and showed attachment to the exoskeleton and chitinous exuviae. The metabolic focus on andrimid production with chitin indicates that the antibiotic could serve an ecophysiological function. S2052 was compared with two related V. coralliilyticus strains (LMG20984(T) and LMG10953). Despite overall similar secondary metabolomes, LMG20984(T) and LMG10953 did not produce andrimid, and their optimum biosynthetic temperature was 30 as compared with 25°C for S2052. In addition, S2052 appeared less pathogenic towards Artemia than reported for the type strain. Different physiologies of S2052 and closely related strains indicated that V. coralliilyticus subspecies may be adapted to different niches.
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Affiliation(s)
- Matthias Wietz
- National Food Institute, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark. Center for Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark
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Mansson M, Gram L, Larsen TO. Production of bioactive secondary metabolites by marine vibrionaceae. Mar Drugs 2011; 9:1440-1468. [PMID: 22131950 PMCID: PMC3225927 DOI: 10.3390/md9091440] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Revised: 08/11/2011] [Accepted: 08/15/2011] [Indexed: 11/25/2022] Open
Abstract
Bacteria belonging to the Vibrionaceae family are widespread in the marine environment. Today, 128 species of vibrios are known. Several of them are infamous for their pathogenicity or symbiotic relationships. Despite their ability to interact with eukaryotes, the vibrios are greatly underexplored for their ability to produce bioactive secondary metabolites and studies have been limited to only a few species. Most of the compounds isolated from vibrios so far are non-ribosomal peptides or hybrids thereof, with examples of N-containing compounds produced independent of nonribosomal peptide synthetases (NRPS). Though covering a limited chemical space, vibrios produce compounds with attractive biological activities, including antibacterial, anticancer, and antivirulence activities. This review highlights some of the most interesting structures from this group of bacteria. Many compounds found in vibrios have also been isolated from other distantly related bacteria. This cosmopolitan occurrence of metabolites indicates a high incidence of horizontal gene transfer, which raises interesting questions concerning the ecological function of some of these molecules. This account underlines the pending potential for exploring new bacterial sources of bioactive compounds and the challenges related to their investigation.
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Affiliation(s)
- Maria Mansson
- Center from Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, Søltofts Plads 221, DK-2800 Kgs. Lyngby, Denmark; E-Mail:
| | - Lone Gram
- National Food Institute, Technical University of Denmark, Søltofts Plads 221, DK-2800 Kgs. Lyngby, Denmark; E-Mail:
| | - Thomas O. Larsen
- Center from Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, Søltofts Plads 221, DK-2800 Kgs. Lyngby, Denmark; E-Mail:
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Wietz M, Mansson M, Gotfredsen CH, Larsen TO, Gram L. Antibacterial compounds from marine Vibrionaceae isolated on a global expedition. Mar Drugs 2010; 8:2946-60. [PMID: 21339958 PMCID: PMC3039463 DOI: 10.3390/md8122946] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2010] [Revised: 12/01/2010] [Accepted: 12/09/2010] [Indexed: 12/19/2022] Open
Abstract
On a global research expedition, over 500 bacterial strains inhibitory towards pathogenic bacteria were isolated. Three hundred of the antibacterial strains were assigned to the Vibrionaceae family. The purpose of the present study was to investigate the phylogeny and bioactivity of five Vibrionaceae strains with pronounced antibacterial activity. These were identified as Vibrio coralliilyticus (two strains), V. neptunius (two strains), and Photobacterium halotolerans (one strain) on the basis of housekeeping gene sequences. The two related V. coralliilyticus and V. neptunius strains were isolated from distant oceanic regions. Chemotyping by LC-UV/MS underlined genetic relationships by showing highly similar metabolite profiles for each of the two V. coralliilyticus and V. neptunius strains, respectively, but a unique profile for P. halotolerans. Bioassay-guided fractionation identified two known antibiotics as being responsible for the antibacterial activity; andrimid (from V. coralliilyticus) and holomycin (from P. halotolerans). Despite the isolation of already known antibiotics, our findings show that marine Vibrionaceae are a resource of antibacterial compounds and may have potential for future natural product discovery.
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Affiliation(s)
- Matthias Wietz
- National Food Institute, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark; E-Mail:
| | - Maria Mansson
- Centre for Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark; E-Mails: (M.M.); (T.O.L.)
| | - Charlotte H. Gotfredsen
- Department of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark; E-Mail:
| | - Thomas O. Larsen
- Centre for Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark; E-Mails: (M.M.); (T.O.L.)
| | - Lone Gram
- National Food Institute, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark; E-Mail:
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Prateeptongkum S, Driller K, Jackstell R, Spannenberg A, Beller M. Efficient Synthesis of Biologically Interesting 3,4-Diaryl-Substituted Succinimides and Maleimides: Application of Iron-Catalyzed Carbonylations. Chemistry 2010; 16:9606-15. [DOI: 10.1002/chem.201000369] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Thomas TRA, Kavlekar DP, LokaBharathi PA. Marine drugs from sponge-microbe association--a review. Mar Drugs 2010; 8:1417-68. [PMID: 20479984 PMCID: PMC2866492 DOI: 10.3390/md8041417] [Citation(s) in RCA: 255] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2010] [Revised: 04/13/2010] [Accepted: 04/19/2010] [Indexed: 12/31/2022] Open
Abstract
The subject of this review is the biodiversity of marine sponges and associated microbes which have been reported to produce therapeutically important compounds, along with the contextual information on their geographic distribution. Class Demospongiae and the orders Halichondrida, Poecilosclerida and Dictyoceratida are the richest sources of these compounds. Among the microbial associates, members of the bacterial phylum Actinobacteria and fungal division Ascomycota have been identified to be the dominant producers of therapeutics. Though the number of bacterial associates outnumber the fungal associates, the documented potential of fungi to produce clinically active compounds is currently more important than that of bacteria. Interestingly, production of a few identical compounds by entirely different host-microbial associations has been detected in both terrestrial and marine environments. In the Demospongiae, microbial association is highly specific and so to the production of compounds. Besides, persistent production of bioactive compounds has also been encountered in highly specific host-symbiont associations. Though spatial and temporal variations are known to have a marked effect on the quality and quantity of bioactive compounds, only a few studies have covered these dimensions. The need to augment production of these compounds through tissue culture and mariculture has also been stressed. The reviewed database of these compounds is available at www.niobioinformatics.in/drug.php.
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Affiliation(s)
- Tresa Remya A. Thomas
- Biological Oceanography, National Institute of Oceanography, Dona Paula, Goa, Pin-403004, India; E-Mails:
(T.R.A.T.);
(D.P.K.)
| | - Devanand P. Kavlekar
- Biological Oceanography, National Institute of Oceanography, Dona Paula, Goa, Pin-403004, India; E-Mails:
(T.R.A.T.);
(D.P.K.)
| | - Ponnapakkam A. LokaBharathi
- Biological Oceanography, National Institute of Oceanography, Dona Paula, Goa, Pin-403004, India; E-Mails:
(T.R.A.T.);
(D.P.K.)
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Adib M, Ansari S, Fatemi S, Bijanzadeh HR, Zhu LG. A multi-component synthesis of 3-aryl-1-(arylmethylideneamino)pyrrolidine-2,5-diones. Tetrahedron 2010. [DOI: 10.1016/j.tet.2010.01.108] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Rahman H, Austin B, Mitchell WJ, Morris PC, Jamieson DJ, Adams DR, Spragg AM, Schweizer M. Novel anti-infective compounds from marine bacteria. Mar Drugs 2010; 8:498-518. [PMID: 20411112 PMCID: PMC2857357 DOI: 10.3390/md8030498] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2010] [Revised: 03/01/2010] [Accepted: 03/02/2010] [Indexed: 11/16/2022] Open
Abstract
As a result of the continuous evolution of microbial pathogens towards antibiotic-resistance, there have been demands for the development of new and effective antimicrobial compounds. Since the 1960s, the scientific literature has accumulated many publications about novel pharmaceutical compounds produced by a diverse range of marine bacteria. Indeed, marine micro-organisms continue to be a productive and successful focus for natural products research, with many newly isolated compounds possessing potentially valuable pharmacological activities. In this regard, the marine environment will undoubtedly prove to be an increasingly important source of novel antimicrobial metabolites, and selective or targeted approaches are already enabling the recovery of a significant number of antibiotic-producing micro-organisms. The aim of this review is to consider advances made in the discovery of new secondary metabolites derived from marine bacteria, and in particular those effective against the so called "superbugs", including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE), which are largely responsible for the increase in numbers of hospital acquired, i.e., nosocomial, infections.
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Affiliation(s)
- Hafizur Rahman
- School of Life Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, Scotland, UK; E-Mails:
(H.R.);
(W.J.M.);
(P.C.M.);
(D.J.J.);
(M.S.)
| | - Brian Austin
- School of Life Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, Scotland, UK; E-Mails:
(H.R.);
(W.J.M.);
(P.C.M.);
(D.J.J.);
(M.S.)
- Institute of Aquaculture, University of Stirling, Stirling, FK9 4LA, Scotland, UK
| | - Wilfrid J. Mitchell
- School of Life Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, Scotland, UK; E-Mails:
(H.R.);
(W.J.M.);
(P.C.M.);
(D.J.J.);
(M.S.)
| | - Peter C. Morris
- School of Life Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, Scotland, UK; E-Mails:
(H.R.);
(W.J.M.);
(P.C.M.);
(D.J.J.);
(M.S.)
| | - Derek J. Jamieson
- School of Life Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, Scotland, UK; E-Mails:
(H.R.);
(W.J.M.);
(P.C.M.);
(D.J.J.);
(M.S.)
| | - David R. Adams
- Department of Chemistry, School of Engineering and Physical Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, Scotland, UK; E-Mail:
(D.R.A.)
| | - Andrew Mearns Spragg
- Aquapharm Biodiscovery Limited, European Centre for Marine Biotechnology, Dunstaffnage Marine Laboratory, Oban, Argyll PA37 1QA, Scotland, UK; E-Mail:
(A.M.S.)
| | - Michael Schweizer
- School of Life Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, Scotland, UK; E-Mails:
(H.R.);
(W.J.M.);
(P.C.M.);
(D.J.J.);
(M.S.)
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Antibiotics from microbes: converging to kill. Curr Opin Microbiol 2009; 12:520-7. [PMID: 19695947 DOI: 10.1016/j.mib.2009.07.002] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2009] [Revised: 07/06/2009] [Accepted: 07/08/2009] [Indexed: 11/20/2022]
Abstract
As genetically encoded small molecules, antibiotics are phenotypes that have resulted from mutation and natural selection. Advances in genetics, biochemistry, and bioinformatics have connected hundreds of antibiotics to the gene clusters that encode them, allowing these molecules to be analyzed using the tools of evolutionary biology. This review surveys examples of convergent evolution from microbially produced antibiotics, including the convergence of distinct gene clusters on similar phenotypes and the merger of distinct gene clusters into a single functional unit. Examining antibiotics through an evolutionary lens highlights the versatility of biosynthetic pathways, reveals lessons for combating antibiotic resistance, and provides an entry point for studying the natural roles of these natural products.
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Isnansetyo A, Kamei Y. Bioactive substances produced by marine isolates of Pseudomonas. J Ind Microbiol Biotechnol 2009; 36:1239-48. [PMID: 19582493 DOI: 10.1007/s10295-009-0611-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2009] [Accepted: 06/16/2009] [Indexed: 11/24/2022]
Abstract
Pseudomonas is a genus of non-fermentative gram-negative Gammaproteobacteria found both on land and in the water. Many terrestrial isolates of this genus have been studied extensively. While many produce bioactive substances, enzymes, and biosurfactants, other Pseudomonas isolates are used for biological control of plant diseases and bioremediation. In contrast, only a few marine isolates of this genus have been described that produce novel bioactive substances. The chemical structures of the bioactive substances from marine Pseudomonas are diverse, including pyroles, pseudopeptide pyrrolidinedione, phloroglucinol, phenazine, benzaldehyde, quinoline, quinolone, phenanthren, phthalate, andrimid, moiramides, zafrin and bushrin. Some of these bioactive compounds are antimicrobial agents, and dibutyl phthalate and di-(2-ethylhexyl) phthalate have been reported to be cathepsin B inhibitors. In addition to being heterogeneous in terms of their structures, the antibacterial substances produced by Pseudomonas also have diverse mechanisms of action: some affect the bacterial cell membrane, causing bacterial cell lysis, whereas others act as acetyl-CoA carboxylase and nitrous oxide synthesis inhibitors. Marine Pseudomonas spp. have been isolated from a wide range of marine environments and are a potential untapped source for medically relevant bioactive substances.
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Affiliation(s)
- Alim Isnansetyo
- Department of Fisheries, Faculty of Agriculture, Gadjah Mada University, Jl. Flora Bulaksumur, Yogyakarta 55182, Indonesia.
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