Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Center for Drug Design Discovery and Development (C4D), SRM University, Delhi NCR, Sonepat, Haryana, India.
Antimicrob Agents Chemother. 2019 Jun 24;63(7). doi: 10.1128/AAC.00343-19. Print 2019 Jul.
Indole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall-associated mycolic acid transporter of In the present study, we characterized indoleamide effects on bacterial cell morphology and reevaluated pharmacokinetics and efficacy using an optimized oral formulation. Morphologically, indoleamide-treated cells demonstrated significantly higher numbers of dimples near the poles or septum, which may serve as the mechanism of cell death for this bactericidal scaffold. Using the optimized formulation, an expanded-spectrum indoleamide, compound 2, showed significantly improved pharmacokinetic (PK) parameters and efficacy in mouse infection models. In a comparative study, compound 2 showed superior efficacy over compound 3 (NITD-304) in a high-dose aerosol mouse infection model. Since indoleamides are equally active on drug-resistant , these findings demonstrate the therapeutic potential of this novel scaffold for the treatment of both drug-susceptible and drug-resistant tuberculosis.
吲哚-2-甲酰胺衍生物是 MmpL3 的抑制剂，MmpL3 是细胞壁相关的分枝菌酸转运蛋白。在本研究中，我们对吲哚酰胺对细菌细胞形态的影响进行了表征，并使用优化的口服制剂重新评估了其药代动力学和疗效。形态学上，用吲哚酰胺处理的细胞在极或隔膜附近显示出明显更多的小凹坑，这可能是这种杀菌支架的细胞死亡机制。使用优化的制剂，一种扩展谱的吲哚酰胺化合物 2 在小鼠感染模型中表现出显著改善的药代动力学（PK）参数和疗效。在一项比较研究中，化合物 2 在高剂量雾化小鼠感染模型中显示出优于化合物 3（NITD-304）的疗效。由于吲哚酰胺对耐药性同样有效，这些发现表明这种新型支架在治疗耐药和敏感结核病方面具有治疗潜力。
