Turning Defense into Offense: Defensin Mimetics as Novel Antibiotics Targeting Lipid II

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.

Efficacy of the small molecule inhibitor of Lipid II BAS00127538 against Acinetobacter baumannii

“…Here, we report for the first time any Lipid II inhibitor with activity against A. baumannii . Compound BAS00127538 specifically and uniquely interacts with the N-acetyl muramic acid moeity and isoprenyl tail of Lipid II with additional predicted interactions with the Lipid II phosphate moiety 10. BAS00127538 was found to affect cell wall biosynthesis with membrane perturbation as a likely secondary mechanism-of-action 10.…”

“…Compound BAS00127538 specifically and uniquely interacts with the N-acetyl muramic acid moeity and isoprenyl tail of Lipid II with additional predicted interactions with the Lipid II phosphate moiety 10. BAS00127538 was found to affect cell wall biosynthesis with membrane perturbation as a likely secondary mechanism-of-action 10. Colistin is believed to act by competitive displacement of divalent cations from the phosphate groups of membrane lipids and by binding to lipopolysaccharides in the outer cell membrane of Gram-negative bacteria 14,15.…”

“…Factors that contribute to pathogenesis of this organism include iron acquisition, membrane polysaccharides and vesicles, biofilm formation, and penicillin-binding proteins 9. We have recently described small molecule inhibitors of Lipid II for the first time 10. Our most promising compound, BAS00127538, was highly active against Gram-positive species and showed activity against Gram-negative species also, albeit reduced.…”

“…Our most promising compound, BAS00127538, was highly active against Gram-positive species and showed activity against Gram-negative species also, albeit reduced. This compound binds to Lipid II differently than other compounds, affects cell wall biosynthesis, and showed efficacy in vivo 10. Since vancomycin, dalbavancin, and oritavancin fail to demonstrate any notable activity against A. baumannii , we tested activity of our lead small molecule Lipid II inhibitor BAS00127538 (Figure 1) against this species.…”

Defense peptides: recent developments

“…Similarly to AMPs, such properties as cationicity and hydrophobicity of these synthetic molecules can be appropriately modified in order to obtain peptidomimetics with Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 7/27/15 1:57 AM desired activity. Recently, a human defensin mimetic that binds lipid II involved in bacterial PGN synthesis has been designed and demonstrated to be protective in an in vivo murine model of sepsis caused by S. aureus (101). Furthermore, Ryan et al (102) developed nonpeptide mimetics, which were highly active and selective against C. albicans when tested in mouse models of oral candidiasis.…”