Mycobacterium tuberculosis(Mtb) must sense and adapt to immune pressures such as acidic pH during pathogenesis. The goal of this study was to isolate compounds that inhibit acidic pH resistance, thus defining virulence pathways that are vulnerable to chemotherapy. Here, we report that the compound AC2P36 selectively kills Mtb at acidic pH and potentiates the bactericidal activity of isoniazid, clofazimine, and diamide. We show that AC2P36 activity is associated with thiol stress and causes an enhanced accumulation of intracellular reactive oxygen species at acidic pH. Mechanism of action studies demonstrate that AC2P36 directly depletes Mtb thiol pools, with enhanced depletion of free thiols at acidic pH. These findings support that Mtb is especially vulnerable to thiol stress at acidic pH and that chemical depletion of thiol pools is a promising target to promote Mtb killing and potentiation of antimicrobials.

中文翻译：

---

靶向结核分枝杆菌对酸性pH值对硫醇胁迫的敏感性杀死细菌并增强抗生素作用

结核分枝杆菌（Mtb）必须在发病过程中感知并适应免疫压力，例如酸性pH。这项研究的目的是分离抑制酸性pH耐受性的化合物，从而确定对化学疗法敏感的毒力途径。在这里，我们报道化合物AC2P36在酸性pH下选择性杀灭Mtb，并增强异烟肼，氯法齐明和二酰胺的杀菌活性。我们表明，AC2P36活性与硫醇胁迫相关联，并导致在酸性pH值下细胞内活性氧物种的积累增加。作用机理研究表明，AC2P36直接消耗Mtb硫醇池，并在酸性pH下增加了游离硫醇的消耗。