Franz Nicholas D, Belardinelli Juan Manuel, Kaminski Michael A, Dunn Louis C, Calado Nogueira de Moura Vinicius, Blaha Michael A, Truong Dan D, Li Wei, Jackson Mary, North E Jeffrey
Department of Pharmacy Sciences, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
Bioorg Med Chem. 2017 Jul 15;25(14):3746-3755. doi: 10.1016/j.bmc.2017.05.015. Epub 2017 May 8.
Current treatment regimens for non-tuberculous mycobacteria (NTM) and tuberculosis (TB) generally require long duration of therapy with multiple drugs, some of which are broad spectrum antibiotics. Despite some advances in antimicrobial compounds, there remains a need in therapy for antibiotics with specific mycobacterial targets. It has been shown that MmpL3 is an essential transporter required for the translocation of mycolic acids to the mycobacterial cell envelope. Here, we synthesized a series of indole-2-carboxamides that inhibit MmpL3 and have potent pan-activity against mycobacterial species. The compounds were tested against several fast and slow-growing Mycobacterium species, including M. abscessus, M. massiliense, M. bolletii, M. chelonae, M. tuberculosis, M. avium, M. xenopi and M. smegmatis. The target of these indole-based compounds makes them selective for mycobacteria, while showing no clinically relevant bactericidal activity against S. aureus or P. aeruginosa. These compounds were tested against THP-1, a human-cell line, and showed minimal in vitro cytotoxicity and good selectivity indices. The data shown and discussed suggest that lead indole-2-carboxamides are strong contenders for further preclinical testing as NTM therapeutics.
目前针对非结核分枝杆菌（NTM）和结核病（TB）的治疗方案通常需要使用多种药物进行长时间治疗，其中一些是广谱抗生素。尽管抗菌化合物有了一些进展，但仍需要针对分枝杆菌有特定靶点的抗生素用于治疗。已表明MmpL3是将分枝菌酸转运至分枝杆菌细胞壁所必需的一种重要转运蛋白。在此，我们合成了一系列抑制MmpL3且对分枝杆菌具有强效泛活性的吲哚-2-羧酰胺。这些化合物针对几种快速生长和缓慢生长的分枝杆菌进行了测试，包括脓肿分枝杆菌、马赛分枝杆菌、博列特分枝杆菌、龟分枝杆菌、结核分枝杆菌、鸟分枝杆菌、偶发分枝杆菌和耻垢分枝杆菌。这些基于吲哚的化合物的靶点使其对分枝杆菌具有选择性，同时对金黄色葡萄球菌或铜绿假单胞菌无临床相关杀菌活性。这些化合物针对人细胞系THP-1进行了测试，显示出最小的体外细胞毒性和良好的选择性指数。所示及讨论的数据表明，先导吲哚-2-羧酰胺作为NTM治疗药物，是进一步临床前测试的有力候选者。
