Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32
Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32
复制标题
DOI：
10.1073/pnas.1302114110
复制
发表时间：
2013-07-09
影响因子：
11.1
通讯作者：
Hung, Deborah T.
中科院分区：
文献类型：
--
作者：
Stanley, Sarah A.;Kawate, Tomohiko;Hung, Deborah T.
细菌病原体结核分枝杆菌的感染给全球公共卫生带来了巨大负担。迫切需要新的抗生素来对抗全球结核病大流行;然而，由于缺乏经过验证的药物靶标，新的小分子药物的开发受到阻碍。在这里，我们描述了一个4，6-二芳基-5，7-二甲基香豆素系列，杀死M。通过抑制脂肪酸降解蛋白D32（FadD 32）来治疗结核病，脂肪酸降解蛋白D32是细胞壁分枝菌酸的生物合成所需的酶。这些取代的香豆素抑制剂直接抑制FadD 32的酰基-酰基载体蛋白合成酶活性。它们在体外和结核病动物模型中有效地阻断细菌复制，验证了FadD 32作为抗生素开发的靶点，其作用途径与已建立的抗生素异烟肼相同。在抗结核治疗中，靶向经过充分验证的生物合成途径中的新步骤是一种强有力的策略，它消除了围绕新靶点和体内临床疗效的大部分常见不确定性，同时规避了对既定靶点的现有耐药性。
Infection with the bacterial pathogen Mycobacterium tuberculosis imposes an enormous burden on global public health. New antibiotics are urgently needed to combat the global tuberculosis pandemic; however, the development of new small molecules is hindered by a lack of validated drug targets. Here, we describe the identification of a 4,6-diaryl-5,7-dimethyl coumarin series that kills M. tuberculosis by inhibiting fatty acid degradation protein D32 (FadD32), an enzyme that is required for biosynthesis of cell-wall mycolic acids. These substituted coumarin inhibitors directly inhibit the acyl-acyl carrier protein synthetase activity of FadD32. They effectively block bacterial replication both in vitro and in animal models of tuberculosis, validating FadD32 as a target for antibiotic development that works in the same pathway as the established antibiotic isoniazid. Targeting new steps in well-validated biosynthetic pathways in antitubercular therapy is a powerful strategy that removes much of the usual uncertainty surrounding new targets and in vivo clinical efficacy, while circumventing existing resistance to established targets.