Indolcarboxamide Is a Preclinical Candidate for Treating Multidrug-Resistant Tuberculosis
Indolcarboxamide Is a Preclinical Candidate for Treating Multidrug-Resistant Tuberculosis
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DOI：
10.1126/scitranslmed.3007355
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发表时间：
2013-12-04
影响因子：
17.1
通讯作者：
Manjunatha, Ujjini H.
中科院分区：
文献类型：
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作者：
Rao, Srinivasa P. S.;Lakshminarayana, Suresh B.;Manjunatha, Ujjini H.
抗多药耐药结核分枝杆菌(Mtb)的化疗药物迫切需要新的化合物来对抗结核病的耐药性。我们鉴定并表征了吲哚碳酰胺类新型抗结核杀菌剂。遗传和脂谱研究确定吲哚碳酰胺的可能分子靶标是MmpL3，一种对分枝杆菌细胞壁生物合成至关重要的海藻糖单菌酸酯的转运体。两个主要候选菌株NITD-304和NITD-349对药物敏感和多药耐药的临床分离株都显示出很强的活性。这两种化合物在几个物种中口服后有希望的药代动力学曲线使进一步的疗效和安全性评估成为可能。NITD-304和NITD-349对小鼠急性和慢性结核分枝杆菌感染均有治疗作用。此外，在探索性大鼠毒理学研究中，NITD-304和NITD-349连续两周的剂量显示出有希望的安全边际。最后，两种化合物都没有抑制主要的细胞色素P-450酶的活性或HERG(人类乙醚-阿戈-GO相关基因)通道的活性。这些结果表明，NITD-304和NITD-349应进一步开发为治疗耐多药结核病的潜在药物。
New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-ago-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.