An Antibacterial β-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis.

ABSTRACT: The spread of antibiotic resistance is a major challenge for the treatment of Mycobacterium tuberculosis infections. In addition, the efficacy of drugs is often limited by the restricted permeability of the mycomembrane. Frontline antibiotics inhibit mycomembrane biosynthesis, leading to rapid cell death. Inspired by this mechanism, we exploited β-lactones as putative mycolic acid mimics to block serine hydrolases involved in their biosynthesis. Among a collection of β-lactones, we found one hit with potent anti-mycobacterial and bactericidal activity. Chemical proteomics using an alkynylated probe identified Pks13 and Ag85 serine hydrolases as major targets. Validation through enzyme assays and customized ¹³ C metabolite profiling showed that both targets are functionally impai

SUBMITTER: Lehmann J 

PROVIDER: S-EPMC6104829 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature