biostudies-literatureUnknownOmollo CCarnegie Mellon Scholarship AwardsNovartis Research FoundationNorges ForskningsrådStrategic Health Innovations Partnerships Unit of the South African Medical Research CouncilSouth African Medical Research CouncilUniversity of Cape TownTuberculosis (TB) is a leading global cause of mortality owing to an infectious agent, accounting for almost one-third of antimicrobial resistance (AMR) deaths annually. We aimed to identify synergistic anti-TB drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of the causative agent, Mycobacterium tuberculosis We investigated combinations containing the known translational inhibitors, spectinomycin (SPT) and fusidic acid (FA), or the phenothiazine, chlorpromazine (CPZ), which disrupts mycobacterial energy metabolism. Potentiation of whole-cell drug efficacy was observed in SPT-CPZ combinations. This effect was lost against an M. tuberculosis mutant lacking the major facilitator superfamily (MFS) efflux pump, Rv1258c. Notably, the SPT-CPZ comAntimicrobial agents and chemotherapyAAC.02554-20https://www.ebi.ac.uk/biostudies/studies/S-EPMC8092878biostudies-literatureDeveloping synergistic drug combinations to restore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis.PMC8092878Chibale KOmollo CAgarwal PWasuna AMoosa AIoerger TRMizrahi VWarner DFKigondu ESingh VfalseDeveloping synergistic drug combinations to restore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis.Tuberculosis (TB) is a leading global cause of mortality owing to an infectious agent, accounting for almost one-third of antimicrobial resistance (AMR) deaths annually. We aimed to identify synergistic anti-TB drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of the causative agent, Mycobacterium tuberculosis We investigated combinations containing the known translational inhibitors, spectinomycin (SPT) and fusidic acid (FA), or the phenothiazine, chlorpromazine (CPZ), which disrupts mycobacterial energy metabolism. Potentiation of whole-cell drug efficacy was observed in SPT-CPZ combinations. This effect was lost against an M. tuberculosis mutant lacking the major facilitator superfamily (MFS) efflux pump, Rv1258c. Notably, the SPT-CPZ com2021-01-01T00:00:00Z2021 Feb2025-04-26T23:43:07.996Z2025-04-06T17:39:19.166ZS-EPMC80928783361906210.1128/AAC.02554-20