Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
Cell Chem Biol. 2017 Aug 17;24(8):993-1004.e4. doi: 10.1016/j.chembiol.2017.06.018. Epub 2017 Aug 3.
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.
结核分枝杆菌（Mtb）在发病过程中必须感知和适应免疫压力，如酸性 pH 值。本研究的目的是分离抑制酸性 pH 值耐药性的化合物，从而确定易受化疗影响的毒力途径。在这里，我们报告化合物 AC2P36 可在酸性 pH 值下选择性杀死 Mtb 并增强异烟肼、氯法齐明和二脒的杀菌活性。我们表明，AC2P36 的活性与硫醇应激有关，并导致酸性 pH 值下细胞内活性氧的积累增加。作用机制研究表明，AC2P36 直接耗尽 Mtb 的硫醇池，在酸性 pH 值下耗尽游离硫醇。这些发现支持 Mtb 在酸性 pH 值下特别容易受到硫醇应激的影响，并且化学耗尽硫醇池是促进 Mtb 杀伤和增强抗菌药物的有前途的目标。
