Abstract
We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections.
Highlights
The ever-increasing emergence of many pathogenic bacterial strains resistant to commonly used antibiotics is a rapidly growing concern in public health
An increasing number of people are at risk for bacterial infections that cannot be effectively treated
Infection caused by the methicillinresistant Staphylococcus aureus bacterium or MRSA is the cause of many fatalities and puts a burden on health care systems in many countries
Summary
The ever-increasing emergence of many pathogenic bacterial strains resistant to commonly used antibiotics is a rapidly growing concern in public health. Resistant bacteria spread and cause infections at increasing rates, and there is an urgent need to develop novel classes of potent antibiotics against established molecular targets, such as Lipid II. Lipid II is an essential precursor in cell wall biosynthesis It is comprised of a hydrophilic head group that includes a peptidoglycan subunit composed of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) coupled to a short pentapeptide moiety. This headgroup is coupled to a long bactoprenol chain via a pyrophosphate group. Schneider et al [18] characterized the Lipid II binding site
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