In the search for new anti-tuberculosis drugs with novel mechanisms of action, we evaluated the antimycobacterial activity of a panel of eight phenolic acids against four pathogenic mycobacterial model species, including M. tuberculosis. We demonstrated that salicylic acid (SA), as well as the iodinated derivatives 5-iodo-salicylic acid (5ISA) and 3,5-diiodo-salicylic acid (3,5diISA), displayed promising antitubercular activities. Remarkably, using a genetically encoded mycobacterial intrabacterial pH reporter, we describe for the first time that SA, 5ISA, 3,5diISA and the anti-inflammatory drug aspirin (ASP) act by disrupting the intrabacterial pH homeostasis of M. tuberculosis in a dose-dependent manner under in vitro conditions mimicking the endolysosomal pH of macrophages. In contrast, the structurally related second-line anti-TB drug 4-aminosalicylic acid (PAS) had no pH-dependent activity and was strongly antagonized by L-methionine supplementation, thereby suggesting distinct modes of action. Finally, we propose that SA, ASP and its two iodinated derivatives could restrict M. tuberculosis growth in a pH-dependent manner by acidifying the cytosol of the bacilli; therefore, making such compounds very attractive for further development.

中文翻译：

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水杨酸衍生物的抗结核潜力和pH驱动的作用模式


在寻找具有新作用机制的新型抗结核药物的过程中，我们评估了一组八种酚酸对四种致病性分枝杆菌模型物种（包括结核分枝杆菌）的抗分枝杆菌活性。我们证明，水杨酸（SA）以及碘化衍生物5-碘水杨酸（5ISA）和3,5-二碘水杨酸（3,5diISA）表现出良好的抗结核活性。值得注意的是，使用基因编码的分枝杆菌细菌内 pH 报告基因，我们首次描述了 SA、5ISA、3,5diISA 和抗炎药物阿司匹林 (ASP) 通过以一定剂量破坏结核分枝杆菌的细菌内 pH 稳态来发挥作用。在模拟巨噬细胞内溶酶体 pH 的体外条件下依赖的方式。相比之下，结构相关的二线抗结核药物 4-氨基水杨酸 (PAS) 不具有 pH 依赖性活性，并且可被 L-蛋氨酸补充剂强烈拮抗，从而表明不同的作用模式。最后，我们提出SA、ASP及其两种碘化衍生物可以通过酸化杆菌的胞浆以pH依赖的方式限制结核分枝杆菌的生长；因此，此类化合物对于进一步开发非常有吸引力。