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.
Highlights
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 investigated whether this effect resulted from CPZ-mediated disruption of the activity of the major facilitator superfamily (MFS) efflux pump, Rv1258c, which has been implicated in innate resistance to SPT [18]
The synergy detected on exposing wild-type M. tuberculosis to a combination of CPZ and SPT (Fig. 1a) was eliminated in the DRv1258c mutant (Fig. 1b)—which yielded a RFIC value of 0.75 (Table 1)—but was restored in the complemented DRv1258c pCRS4 strain (Fig. 1c), with a RFIC of 0.12 (Table 1)
Summary
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. 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. The antimicrobial-potentiating effect of FA with other antibiotics, including the frontline anti-TB drug ethambutol (EMB), as well as its lack of cross-resistance to other antimicrobial classes, provided additional motivation for our choice of FA [12, 28] By testing these combinations against both drug-susceptible M. tuberculosis H37Rv and selected drugresistant mutants, we explored new potentiating combinations and demonstrated the utility of developing potent combinations against bacilli carrying preexisting genetic resistance to either of the partner drugs. This work revealed that the addition of SPT as third agent to the existing first-line anti-TB drug combination of RIF and INH restores activity in vitro against defined pre-MDR mutants of M. tuberculosis
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