PDF(Pubmed)
Abstract：
The F1FO-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting the FO domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at low nanomolar concentrations against fast- and slow-growing NTM as well as clinical isolates by depleting intrabacterial ATP. As demonstrated for the fast grower Mycobacterium abscessus, the compound is potent in vitro and in vivo, without inducing toxicity. Combining TBAJ-5307 with anti-NTM antibiotics or the oral tebipenem-avibactam pair showed attractive potentiation. Furthermore, the TBAJ-5307-tebipenem-avibactam cocktail kills the pathogen, suggesting a novel oral combination for the treatment of NTM lung infections.
摘要：
F1FO-ATP合酶引擎通过提供生物能量ATP并在低氧胁迫条件下保持ATP稳态，对于非结核分枝杆菌（NTM）的生存能力和生长至关重要。这里,我们报道了二芳基喹啉TBAJ-5307作为广谱抗NTM抑制剂的发现，瞄准发动机的FO域，防止旋转和质子移位。TBAJ-5307在低纳摩尔浓度下对快速和缓慢生长的NTM以及通过消耗细菌内ATP的临床分离株具有活性。正如快速生长的脓肿分枝杆菌所证明的那样，该化合物在体外和体内都是有效的，不诱导毒性。TBAJ-5307与抗NTM抗生素或口服替比培南-阿维巴坦对的组合显示出诱人的增强作用。此外，TBAJ-5307-替比培南-阿维巴坦鸡尾酒杀死病原体，提出了一种治疗NTM肺部感染的新型口服组合。
