Developing synergistic drug combinations to restore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis
Developing synergistic drug combinations to restore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis
ABSTRACT Mycobacterium tuberculosis is the leading global cause of death owing to an infectious agent, accounting for approximately one in four antimicrobial resistance (AMR) fatalities annually. In this study, we aimed to identify synergistic drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of M. tuberculosis. To this end, we investigated combinations containing the known translational inhibitors, spectinomycin (SPT) and fusidic acid (FA), or the phenothiazine antibiotic, chlorpromazine (CPZ), which disrupts mycobacterial energy metabolism. Potentiation was observed between SPT and CPZ. This effect was lost against an M. tuberculosis mutant lacking the major facilitator superfamily (MFS) efflux pump, Rv1258c. Notably, the SPT-CPZ combination restored SPT efficacy against an SPT-resistant mutant carrying a g1379t point mutation in rrs, encoding the mycobacterial 16S ribosomal RNA. Combinations of SPT with FA, which targets the mycobacterial elongation factor G (EF-G), exhibited potentiating activity against wild-type M. tuberculosis. Moreover, this combination produced a small potentiating effect against defined FA-monoresistant and SPT-monoresistant mutants. Finally, combining SPT with the frontline anti-tuberculosis (TB) drugs, rifampicin and isoniazid, resulted in enhanced activity in vitro and ex vivo against both drug-susceptible M. tuberculosis and a RIF-monoresistant rpoB S531L mutant. These results provide evidence of the utility of novel potentiating drug combinations in restoring susceptibility against M. tuberculosis strains carrying genetic resistance to any one of the partner drugs.
Chibale Kelly、Mizrahi Valerie、Warner Digby F.、Omollo Charles、Kigondu Elizabeth、Singh Vinayak、Ioerger Thomas R.、Agarwal Pooja、Moosa Atica、Wasuna Antonina
Department of Chemistry, University of Cape Town||SAMRC Drug Discovery and Development Research Unit, University of Cape Town||Institute of Infectious Disease & Molecular Medicine, University of Cape Town||H3D Drug Discovery and Development Centre, University of Cape TownSAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape Town||Institute of Infectious Disease & Molecular Medicine, University of Cape Town||Wellcome Centre for Infectious Diseases Research in Africa, University of Cape TownSAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape Town||Institute of Infectious Disease & Molecular Medicine, University of Cape Town||Wellcome Centre for Infectious Diseases Research in Africa, University of Cape TownDepartment of Chemistry, University of Cape Town||SAMRC Drug Discovery and Development Research Unit, University of Cape Town||SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape Town||Institute of Infectious Disease & Molecular Medicine, University of Cape TownDepartment of Chemistry, University of Cape Town||SAMRC Drug Discovery and Development Research Unit, University of Cape Town||SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape TownDepartment of Chemistry, University of Cape Town||SAMRC Drug Discovery and Development Research Unit, University of Cape Town||SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape Town||Institute of Infectious Disease & Molecular Medicine, University of Cape Town||H3D Drug Discovery and Development Centre, University of Cape TownTexas A&M University, Department of Computer ScienceSAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape Town||Institute of Infectious Disease & Molecular Medicine, University of Cape TownSAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape Town||Institute of Infectious Disease & Molecular Medicine, University of Cape TownDepartment of Chemistry, University of Cape Town||SAMRC Drug Discovery and Development Research Unit, University of Cape Town||SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape Town
医药卫生理论医学研究方法药学
Chibale Kelly,Mizrahi Valerie,Warner Digby F.,Omollo Charles,Kigondu Elizabeth,Singh Vinayak,Ioerger Thomas R.,Agarwal Pooja,Moosa Atica,Wasuna Antonina.Developing synergistic drug combinations to restore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/860288.点此复制
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