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

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 stru...

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Bibliographic Details
Published in:PLoS pathogens 2013-11, Vol.9 (11), p.e1003732
Main Authors: Varney, Kristen M, Bonvin, Alexandre M J J, Pazgier, Marzena, Malin, Jakob, Yu, Wenbo, Ateh, Eugene, Oashi, Taiji, Lu, Wuyuan, Huang, Jing, Diepeveen-de Buin, Marlies, Bryant, Joseph, Breukink, Eefjan, Mackerell, Jr, Alexander D, de Leeuw, Erik P H
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibiotics
Bacteria
Bacterial infections
Binding sites
Biomimetics
Biosynthesis
Defensins - chemistry
Defensins - pharmacology
Dosage and administration
Drug Delivery Systems
Host-parasite relationships
Humans
Indoles - chemistry
Indoles - pharmacology
Lipid metabolism
Lipids
Methicillin-Resistant Staphylococcus aureus
Microbiology
Molecular weight
Nosocomial infections
Peptides
Peptidomimetics - chemistry
Peptidomimetics - pharmacology
Proteins
Pyrans - chemistry
Pyrans - pharmacology
Staphylococcal Infections - drug therapy
Staphylococcus infections
Studies
Uridine Diphosphate N-Acetylmuramic Acid - analogs & derivatives
Uridine Diphosphate N-Acetylmuramic Acid - antagonists & inhibitors
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1003732