Antibiotic target discovery by integrated phenotypic and activity-based profiling of electrophilic fragments.

ABSTRACT: The emergence of antibiotic resistance necessitates the discovery of novel bacterial targets and antimicrobial agents. Here, we present a bacterial target discovery framework that integrates phenotypic screening of cysteine-reactive fragments with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits. Using this approach, we identify β-ketoacyl-acyl carrier protein synthase III (FabH) and MiaA tRNA prenyltransferase as primary targets of a hit fragment, 10-F05, that confer bacterial stress resistance and virulence in Shigella flexneri. Mechanistic investigations elucidate that covalent C112 modification in FabH, an enzyme involved in bacterial fatty acid synthesis, results in its inactivation and consequent growth inhibition. We fur

SUBMITTER: Jin Y 

PROVIDER: S-EPMC11995724 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature