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

PLoS Pathogens

Taiji Oashi¹  Wenbo Yu¹  Alexander D. MacKerell Jr¹  Jing Huang¹  Erik P. H. de Leeuw²  Joseph Bryant²  Eugene Ateh²  Wuyuan Lu²  Marzena Pazgier²  Jakob Malin³  Kristen M. Varney⁴  Alexandre M. J. J. Bonvin⁵  Eefjan Breukink⁵  Marlies Diepeveen-de Buin⁵ 

[1] Department of Pharmaceutical Sciences and Computer-Aided Drug Design Center, University of Maryland, School of Pharmacy, Baltimore, Maryland, United States of America;Institute of Human Virology & Department of Biochemistry and Molecular Biology of the University of Maryland Baltimore School of Medicine, Baltimore, Maryland, United States of America;Maastricht University Medical Center, Maastricht, The Netherlands;NMR Facility, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, United States of America;Utrecht University, Bijvoet Center for Biomolecular Research, Faculty of Science-Chemistry, Utrecht, The Netherlands

关键词: Lipids;    Defensins;    Antibiotics;    Lipid structure;    Staphylococcus aureus;    Dimers (Chemical physics);    Crystal structure;    Cell walls;   

DOI  :  10.1371/journal.ppat.1003732

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY