Lack of new antiinfective agents: Passing into the pre-antibiotic age?

Figure 1 New systemic antibacterial agents approved by the United States Food and Drug Administration per 5-year period, through 2012. From Boucher et al[6], with permission by Oxford Press.

Figure 2 Mechanisms of lipopolysaccharide-induced cytokine (mediator) secretion with subsequent induction of inflammation and sepsis. Without therapeutical intervention, the interaction of the toxins leads to cell activation with subsequent release of inflammation-inducing compounds eventually resulting in sepsis. Intervention strategies may be performed by e.g., AMP and LPS/LP-neutralizers. LPS: Lipopolysaccharide; IL: Interleukin; TNF: Tumor necrosis factor.

Figure 3 Determination of tumor necrosis factor-α expression levels from human lung tissue with lipopolysaccharide from Salmonella minnesota R60 and heat-killed MRSA combined with different concentrations of Pep19-2. 5 (Aspidasept^®). Depicted is the mean ± SEM of 5 independent experiments. Assuming parametric distribution data were log-transformed and groups were compared for statistical significant differences by use of One-Way Repeated Measure ANOVA (^aP < 0.05). From[19] with permission of American Society for Microbiology. LPS: Lipopolysaccharide; TNF: Tumor necrosis factor.

Figure 4 Compound Aspidasept^® (Amino acid sequence GCKKYRRFRWKFKGKFWFWG; EU, United States, and Japan patent filed) is able to inhibit very efficiently the cytokine production induced by the pathogenicity factors endotoxin/lipoproteins or by the bacteria in vitro, in vivo (various mouse models), and ex vivo (human lung, see Figure 3). These inhibition properties of Aspidasept^® comprise various relevant bacterial strains from Gram-negative and Gram-positive origin, as well as Mycobacteria, in particular M. tuberculosis. Aspidasept^® has low toxicity (the NOAEL, no observed adverse effect level’ is 200 to 500 times higher than the planned therapeutical doses). Beside its inflammation-inhibiting activity, it is able to bind the multi-resistant bacteria thus limiting their spreading. LPS: Lipopolysaccharide.