The efficacies of all antibiotics against tuberculosis are eventually eroded by resistance. New strategies to discover drugs or drug combinations with higher barriers to resistance are needed. Previously, we reported the application of a large-scale chemical-genetic interaction screening strategy called PROSPECT (PRimary screening Of Strains to Prioritize Expanded Chemistry and Targets) for the discovery of new Mycobacterium tuberculosis inhibitors, which resulted in the identification of the small molecule BRD-8000, an inhibitor of a novel target, EfpA [ Johnson et al. ( 2019 ) Nature 517 , 72 ]. Leveraging the chemical genetic interaction profile of BRD-8000, we identified BRD-9327, another structurally distinct small molecule EfpA inhibitor. We show that the two compounds are synergistic and display collateral sensitivity because of their distinct modes of action and resistance mechanisms. High-level resistance to one increases the sensitivity to and reduces the emergence of resistance to the other. Thus, the combination of BRD-9327 and BRD-8000 represents a proof-of-concept for the novel strategy of leveraging chemical genetics in the design of antimicrobial combination chemotherapy in which mutual collateral sensitivity is exploited.

中文翻译：

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大规模的化学遗传策略使分枝杆菌中抗菌药物联合化疗的设计成为可能。

最终所有抗生素对结核病的抵抗力都会受到侵蚀。需要新的策略来发现具有更高耐药性障碍的药物或药物组合。以前，我们报道了一种名为PROSPECT（菌株的初步筛选以优先考虑扩展的化学物质和靶标）的大规模化学-遗传相互作用筛选策略在发现新的结核分枝杆菌抑制剂中的应用，从而鉴定了小分子BRD -8000，一种新型靶标EfpA的抑制剂[Johnson等。（2019）自然517，72]。利用BRD-8000的化学遗传相互作用图谱，我们鉴定出BRD-9327，这是另一种结构独特的小分子EfpA抑制剂。我们显示这两种化合物具有协同作用，并且由于其独特的作用方式和耐药机制而显示出附带敏感性。对一个电阻的高电平电阻会增加对另一个电阻的灵敏度，并减少对另一个电阻的出现。因此，BRD-9327和BRD-8000的组合代表了利用化学遗传学设计抗微生物组合化学疗法的新策略的概念证明，在这种化学疗法中，利用了共同的敏感性。