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 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.
NMR Facility, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, United States of America.
Kristen M
KM
Varney
Alexandre M J J
AM
Bonvin
Marzena
M
Pazgier
Jakob
J
Malin
Wenbo
W
Yu
Eugene
E
Ateh
Taiji
T
Oashi
Wuyuan
W
Lu
Jing
J
Huang
Marlies
M
Diepeveen-de Buin
Joseph
J
Bryant
Eefjan
E
Breukink
Alexander D
AD
Mackerell
Erik P H
EP
de Leeuw
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D023082:Defensins / Q000737:chemistry* / Q000494:pharmacology; D016503:Drug Delivery Systems; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology; D011714:Pyrans / Q000737:chemistry* / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors
D000900:Anti-Bacterial Agents; C000597298:BAS00127538; D023082:Defensins; D007211:Indoles; D057786:Peptidomimetics; D011714:Pyrans; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol