Omollo Charles, Singh Vinayak, Kigondu Elizabeth, Wasuna Antonina, Agarwal Pooja, Moosa Atica, Ioerger Thomas R, Mizrahi Valerie, Chibale Kelly, Warner Digby F
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
Antimicrob Agents Chemother. 2023 May 1;65(5). doi: 10.1128/AAC.02554-20. Epub 2021 Feb 22.
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, 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 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 , encoding the mycobacterial 16S ribosomal RNA. Combinations of SPT with FA, which targets the mycobacterial elongation factor G, exhibited potentiating activity against wild-type 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 and against both drug-susceptible and a RIF-monoresistant S531L mutant.These results support the utility of novel potentiating drug combinations in restoring antibiotic susceptibility of strains carrying genetic resistance to any one of the partner compounds.
结核病（TB）是全球因感染因子导致死亡的主要原因，每年几乎占抗菌药物耐药性（AMR）死亡人数的三分之一。我们旨在确定具有恢复针对病原体耐药突变体治疗效果能力的协同抗结核药物组合。我们研究了含有已知翻译抑制剂壮观霉素（SPT）和夫西地酸（FA），或破坏分枝杆菌能量代谢的吩噻嗪类药物氯丙嗪（CPZ）的组合。在SPT-CPZ组合中观察到全细胞药物疗效增强。针对缺乏主要转运体超家族（MFS）外排泵Rv1258c的突变体，这种效果消失。值得注意的是，SPT-CPZ组合部分恢复了SPT对携带g1379t点突变的SPT耐药突变体的疗效，该突变位于编码分枝杆菌16S核糖体RNA的基因中。针对靶向分枝杆菌延伸因子G的FA，SPT与之组合对野生型表现出增强活性。此外，该组合对FA单耐药和SPT单耐药突变体均产生适度的增强作用。最后，将SPT与一线抗结核药物利福平（RIF）和异烟肼联合使用，增强了对药物敏感菌以及RIF单耐药S531L突变体的活性。这些结果支持新型增强药物组合在恢复对任何一种伙伴化合物具有遗传抗性的结核菌株抗生素敏感性方面的效用。
