Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents
Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents
复制标题
DOI：
10.1016/j.chembiol.2019.02.013
复制
发表时间：
2019-06-20
影响因子：
8.6
通讯作者：
Wright, Dennis
中科院分区：
文献类型：
--
作者：
Hajian, Behnoush;Scocchera, Eric;Wright, Dennis
叶酸生物合成途径提供了许多尚未在结核病治疗中开发的可药物靶点。在此，我们发现了一系列小分子，它们通过双靶向叶酸途径中的关键酶二氢叶酸还原酶（DHFR）及其功能类似物Rv2671来中断结核分枝杆菌（Mtb）的叶酸代谢。我们还比较了这些化合物与对氨基水杨酸（PAS）的抗叶酸活性。我们发现PAS的生物活性代谢物，除了先前报道的对DHFR的活性外，还能抑制Mtb中黄素依赖性胸苷酸合成酶，这表明该药物具有多靶点作用机制。最后，我们已经证明抗叶酸治疗结核分枝杆菌减少了霉菌酸的产生，很可能是由于活化的甲基循环的扰动。我们得出结论，Mtb中叶酸途径的多靶点与高效的抗分枝杆菌活性相关。
The folate biosynthetic pathway offers many druggable targets that have yet to be exploited in tuberculosis therapy. Herein, we have identified a series of small molecules that interrupt Mycobacterium tuberculosis (Mtb) folate metabolism by dual targeting of dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, and its functional analog, Rv2671. We have also compared the antifolate activity of these compounds with that of para-aminosalicylic acid (PAS). We found that the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase in Mtb, suggesting a multi-targeted mechanism of action for this drug. Finally, we have shown that antifolate treatment in Mtb decreases the production of mycolic acids, most likely due to perturbation of the activated methyl cycle. We conclude that multi-targeting of the folate pathway in Mtb is associated with highly potent anti-mycobacterial activity.