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Antibacterial activity of Questiomycin A against Mycobacterium tuberculosis by directly targeting FabD

ABSTRACT: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health threat, particularly due to the rise of multidrug-resistant TB (MDR-TB). Current treatment limitations highlight the urgent need for new therapeutics to improve efficacy and shorten therapy duration. Through high-throughput screening, we identified Questiomycin A (QM), a phenoxazinone compound with promising anti-tuberculosis activity against drug-sensitive and drug-resistant Mtb strains. Transcriptomic profiling indicated disruption of cell wall-associated pathways, while thermal proteome profiling (TPP) identified fabD (malonyl CoA-acyl carrier protein transacylase, MCAT), a key enzyme in mycolic acid biosynthesis, as a potential target. Surface plasmon resonance (SPR), enzymatic assays, and genetic manipulation confirmed QM directly binds to and inhibits fabD. QM disrupts cell wall integrity, increases permeability, and causes pH imbalance, proton motive force collapse, ultimately resulting in bactericidal effects. These findings reveal that QM targets fabD to compromise cell wall homeostasis in Mtb, providing a foundation for developing novel anti-tubercular agents targeting fabD.

ORGANISM(S): Mycobacterium tuberculosis H37Rv

PROVIDER: GSE311988 | GEO | 2026/02/25

REPOSITORIES: GEO

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