PXD058002-1

PXD058002 is an original dataset announced via ProteomeXchange.

Title	Integrated Phenotypic and Activity-Based Profiling of Electrophilic Fragments Reveals New Targets for Antibiotics Development
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-07_05:01:37.434.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mikail Abbasov
SpeciesList	scientific name: Shigella flexneri S5644; NCBI TaxID: 1210043; scientific name: Bacteria; NCBI TaxID: NCBITaxon:2;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-18 11:32:56	ID requested
⏵ 1	2025-05-07 05:01:38	announced

10.1016/j.chembiol.2025.02.001;

Jin Y, Jana S, Abbasov ME, Lin H, Antibiotic target discovery by integrated phenotypic and activity-based profiling of electrophilic fragments. Cell Chem Biol, 32(3):434-448.e9(2025) [pubmed]

submitter keyword: Phenotypic screening

covalent inhibitor

antibiotics

activity-based protein profiling

FabH

MiaA

PdxY

Mikail E. Abbasov
contact affiliation	Cornell University
contact email	mikail.abbasov@cornell.edu
lab head
Mikail Abbasov
contact affiliation	Cornell University
contact email	abbasovgroupcornell@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD058002
     1. Label: PRIDE project
     2. Name: Integrated Phenotypic and Activity-Based Profiling of Electrophilic Fragments Reveals New Targets for Antibiotics Development