Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II.

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TitleTurning defense into offense: defensin mimetics as novel antibiotics targeting lipid II.
Publication TypeJournal Article
Year of Publication2013
AuthorsVarney, KM, Bonvin, AMJJ, Pazgier, M, Malin, J, Yu, W, Ateh, E, Oashi, T, Lu, W, Huang, J, de Buin, MDiepeveen-, Bryant, J, Breukink, E, Mackerell, AD, de Leeuw, EPH
JournalPLoS Pathog
Date Published2013
KeywordsAnti-Bacterial Agents, Defensins, Drug Delivery Systems, Humans, Indoles, Methicillin-Resistant Staphylococcus aureus, Peptidomimetics, Pyrans, Staphylococcal Infections, Uridine Diphosphate N-Acetylmuramic Acid

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.

Alternate JournalPLoS Pathog.
PubMed ID24244161
PubMed Central IDPMC3820767
Grant ListR21AI092033 / AI / NIAID NIH HHS / United States