Abstract
BACKGROUND 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.
OBJECTIVE We aimed to identify synergistic two-drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of M. tuberculosis.
METHODS Combinations were investigated containing the known translational inhibitors, spectinomycin (SPT) and fusidic acid (FA), or the phenothiazine antibiotic, chlorpromazine (CPZ), which disrupts mycobacterial energy metabolism.
RESULTS 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.
CONCLUSIONS 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.
