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 rRNA. 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.

中文翻译：

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开发协同药物组合以恢复耐药结核分枝杆菌的抗生素敏感性


结核病 (TB) 是全球主要的传染源死亡原因，每年几乎占抗菌素耐药性 (AMR) 死亡人数的三分之一。我们的目的是确定能够恢复针对病原体结核分枝杆菌耐药突变体的治疗效果的协同抗结核药物组合。我们研究了含有已知翻译抑制剂大观霉素 (SPT) 和夫西地酸 (FA) 或吩噻嗪氯丙嗪 (CPZ) 的组合，它们会破坏分枝杆菌的能量代谢。在 SPT-CPZ 组合中观察到全细胞药物功效的增强。对于缺乏主要促进子超家族 (MFS) 外排泵 Rv1258c 的结核分枝杆菌突变体，这种效应消失。值得注意的是，SPT-CPZ 组合部分恢复了针对rrs中携带 g1379t 点突变（编码分枝杆菌 16S rRNA）的 SPT 抗性突变体的 SPT 功效。 SPT 与 FA 的组合以分枝杆菌延伸因子 G 为目标，表现出对抗野生型结核分枝杆菌的增强活性。此外，这种组合对 FA 单抗性和 SPT 单抗性突变体产生了适度的增强作用。最后，将 SPT 与一线抗结核药物利福平 (RIF) 和异烟肼相结合，可增强体外和离体对药物敏感结核分枝杆菌和 RIF 单抗性rpoB S531L 突变体的活性。这些结果支持新型增强药物组合在恢复分枝杆菌抗生素敏感性方面的效用。 对任何一种伙伴化合物具有遗传抗性的结核菌株。