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. 2015 Aug 26;6(3):71-7.
doi: 10.4331/wjbc.v6.i3.71.

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

Affiliations

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

Klaus Brandenburg et al. World J Biol Chem. .

Abstract

The lack of newly developed antibiotics, together with the increase in multi-resistance of relevant pathogenic bacteria in the last decades, represents an alarming signal for human health care worldwide. The number of severely infected persons increases not only in developing but also in highly industrialized countries. This relates in first line to the most severe form of a bacterial infection, sepsis and the septic shock syndrome, with high mortality on critical care units. No particular anti-sepsis drug is available, and the therapy with conventional antibiotics more and more fails to provide a survival benefit. Due to the fact that the pharmaceutical industry has withdrawn to a high degree from the development of anti-infectious agents, a huge challenge for health care is approaching in the 21(st) century. In this article, these problems are outlined and possible alternatives are presented which may be helpful to solve the problem.

Keywords: Antibiotics; Antimicrobial peptides; Antimicrobial resistance; Cytokines; Endotoxins; Inflammation; Lipoproteins; Sepsis.

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Figures

Figure 1
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
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
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
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.

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