Division of Infectious Disease, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA.
Nat Chem Biol. 2013 Aug;9(8):499-506. doi: 10.1038/nchembio.1277. Epub 2013 Jun 16.
We report a new class of thiophene (TP) compounds that kill Mycobacterium tuberculosis by the previously uncharacterized mechanism of Pks13 inhibition. An F79S mutation near the catalytic Ser55 site in Pks13 conferred TP resistance in M. tuberculosis. Overexpression of wild-type Pks13 resulted in TP resistance, and overexpression of the Pks13(F79S) mutant conferred high resistance. In vitro, TP inhibited fatty acyl-AMP loading onto Pks13. TP inhibited mycolic acid biosynthesis in wild-type M. tuberculosis, but it did so to a much lesser extent in TP-resistant M. tuberculosis. TP treatment was bactericidal and equivalent to treatment with the first-line drug isoniazid, but it was less likely to permit emergent resistance. Combined isoniazid and TP treatment resulted in sterilizing activity. Computational docking identified a possible TP-binding groove within the Pks13 acyl carrier protein domain. This study confirms that M. tuberculosis Pks13 is required for mycolic acid biosynthesis, validates it as a druggable target and demonstrates the therapeutic potential of simultaneously inhibiting multiple targets in the same biosynthetic pathway.
我们报告了一类新的噻吩（TP）化合物，它们通过以前未被描述的 Pks13 抑制机制杀死结核分枝杆菌。Pks13 催化 Ser55 位点附近的 F79S 突变赋予结核分枝杆菌对 TP 的抗性。野生型 Pks13 的过表达导致 TP 抗性，而 Pks13(F79S)突变体的过表达赋予高抗性。在体外，TP 抑制了 Pks13 上的酰基辅酶 A-AMP 的加载。TP 抑制了野生型结核分枝杆菌中的分枝菌酸生物合成，但在 TP 抗性结核分枝杆菌中抑制程度要小得多。TP 处理具有杀菌作用，与一线药物异烟肼相当，但不太可能产生耐药性。异烟肼和 TP 联合治疗具有杀菌活性。计算对接确定了 Pks13 酰基辅酶 A 蛋白结构域内可能的 TP 结合槽。本研究证实了结核分枝杆菌 Pks13 是分枝菌酸生物合成所必需的，验证了它作为一个可成药的靶点，并证明了同时抑制同一生物合成途径中的多个靶标在治疗上的潜力。
