ArticleCell chemical biology2025
Antibiotic target discovery by integrated phenotypic and activity-based profiling of electrophilic fragments.
Article in Cell chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Covalent Inhibitors in Antimicrobial Drug Development-Beyond β-Lactams.Molecules (Basel, Switzerland) · 2026Review
- FabH (β-Ketoacyl-ACP Synthase III) -- Promising Novel Antibacterial Target and Its Inhibitors.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Global profiling of arginine reactivity and ligandability in the human proteome.Nature chemistry · 2026Article
- Identifying novel antibiotic targets.Nature reviews. Drug discovery · 2025Article
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Authors and funding
4 authors.
Funding
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 further demonstrate that irreversible C273 modification at the MiaA RNA-protein interaction interface abrogates substrate tRNA binding, attenuating resistance and virulence through decreased translational accuracy. Our findings underscore the efficacy of integrating phenotypic and activity-based profiling of electrophilic fragments to accelerate the identification and pharmacologic validation of new therapeutic targets.
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Registered trials
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