Dataset Information

Integrated Phenotypic and Activity-Based Profiling of Electrophilic Fragments Reveals New Targets for Antibiotics Development

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 FabH -ketoacyl synthase 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.

INSTRUMENT(S):

ORGANISM(S): Bacteria Shigella Flexneri S5644

TISSUE(S): Cell Culture

DISEASE(S): Congenital Diarrhea

SUBMITTER: Mikail Abbasov

LAB HEAD: Mikail E. Abbasov

PROVIDER: PXD058002 | Pride | 2025-05-07

REPOSITORIES: Pride

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			Action	DRS
	KatieBracken_04H22_YJ_1.raw	Raw
	KatieBracken_04H22_YJ_2.raw	Raw
	KatieBracken_04H22_YJ_3.raw	Raw
	KatieBracken_04H22_YJ_4.raw	Raw
	KatieBracken_04H22_YJ_5.raw	Raw

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

Jin Yizhen Y Jana Sadhan S Abbasov Mikail E ME Lin Hening H

Cell chemical biology 20250227 3

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 ...[more]

PMID: 40020665

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