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

Kristen M. Varney, Alexandre M.J.J. Bonvin, Marzena Pazgier, Jakob Malin, Wenbo Yu, Eugene Ateh, Taiji Oashi, Wuyuan Lu, Jing Huang, Marlies Diepeveen-de Buin, Joseph Bryant, Eefjan Breukink, Alexander D. MacKerell, Erik P.H. de Leeuw

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish
Article numbere1003732
JournalPLoS Pathogens
Volume9
Issue number11
DOIs
StatePublished - Nov 2013
Externally publishedYes

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