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Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters.

Abstract：

:Conventional antibiotics are not effective in treating infections caused by drug-resistant or persistent nongrowing bacteria, creating a dire need for the development of new antibiotics. We report that the small molecule nTZDpa, previously characterized as a nonthiazolidinedione peroxisome proliferator-activated receptor gamma partial agonist, kills both growing and persistent Staphylococcus aureus cells by lipid bilayer disruption. S. aureus exhibited no detectable development of resistance to nTZDpa, and the compound acted synergistically with aminoglycosides. We improved both the potency and selectivity of nTZDpa against MRSA membranes compared to mammalian membranes by leveraging synthetic chemistry guided by molecular dynamics simulations. These studies provide key insights into the design of selective and potent membrane-active antibiotics effective against bacterial persisters.

journal_name

ACS Infect Dis

journal_title

ACS infectious diseases

authors

Kim W,Steele AD,Zhu W,Csatary EE,Fricke N,Dekarske MM,Jayamani E,Pan W,Kwon B,Sinitsa IF,Rosen JL,Conery AL,Fuchs BB,Vlahovska PM,Ausubel FM,Gao H,Wuest WM,Mylonakis E

doi

10.1021/acsinfecdis.8b00161

subject

Has Abstract

pub_date

2018-11-09 00:00:00

pages

1540-1545

issue

11

issn

2373-8227

journal_volume

4

pub_type

杂志文章

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