Developing synergistic drug combinations to restore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis

Charles Omollo; Vinayak Singh; Elizabeth Kigondu; Antonina Wasuna; Pooja Agarwal; Atica Moosa; Thomas R Ioerger; Valerie Mizrahi; Kelly Chibale; Digby F Warner

doi:10.1128/AAC.02554-20

Developing synergistic drug combinations to restore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis

Antimicrob Agents Chemother. 2023 May 1;65(5):e02554-20. doi: 10.1128/AAC.02554-20. Epub 2021 Feb 22.

Authors

Charles Omollo^{1

2

3

4}, Vinayak Singh^{5

2

3

4}, Elizabeth Kigondu^{5

2

3}, Antonina Wasuna^{5

2

3}, Pooja Agarwal^{3

4}, Atica Moosa^{3

4}, Thomas R Ioerger⁶, Valerie Mizrahi^{3

4

7}, Kelly Chibale^{5

2

4}, Digby F Warner^{8

4

7}

Affiliations

¹ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa [email protected] [email protected].
² South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
³ SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DSI/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape Town, Rondebosch 7701, South Africa.
⁴ Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
⁵ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
⁶ Texas A&M University, Department of Computer Science, College Station, TX, 77843, USA.
⁷ Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Rondebosch 7701, South Africa.
⁸ SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DSI/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape Town, Rondebosch 7701, South Africa [email protected] [email protected].

Abstract

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 combination partially 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, exhibited potentiating activity against wild-type M. tuberculosis Moreover, this combination produced a modest potentiating effect against both FA-monoresistant and SPT-monoresistant mutants. Finally, combining SPT with the frontline anti-TB agents, rifampicin (RIF) 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 support the utility of novel potentiating drug combinations in restoring antibiotic susceptibility of M. tuberculosis strains carrying genetic resistance to any one of the partner compounds.