Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA.
Global Health Pharma Unit, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0151421. doi: 10.1128/AAC.01514-21. Epub 2021 Oct 4.
Fluoroquinolones-the only clinically used DNA gyrase inhibitors-are effective against tuberculosis (TB) but are in limited clinical use for nontuberculous mycobacteria (NTM) lung infections due to intrinsic drug resistance. We sought to test alternative DNA gyrase inhibitors for anti-NTM activity. Mycobacterium tuberculosis gyrase inhibitors (MGIs), a subclass of novel bacterial topoisomerase inhibitors (NBTIs), were recently shown to be active against the tubercle bacillus. Here, we show that the MGI EC/11716 not only has potent anti-tubercular activity but is active against M. abscessus and M. avium . Focusing on M. abscessus, which causes the most difficult to cure NTM disease, we show that EC/11716 is bactericidal, active against drug-tolerant biofilms, and efficacious in a murine model of M. abscessus lung infection. Based on resistant mutant selection experiments, we report a low frequency of resistance to EC/11716 and confirm DNA gyrase as its target. Our findings demonstrate the potential of NBTIs as anti-M. abscessus and possibly broad-spectrum anti-mycobacterial agents.
氟喹诺酮类药物——唯一临床上使用的 DNA 回旋酶抑制剂——对结核病（TB）有效，但由于固有耐药性，在非结核分枝杆菌（NTM）肺部感染中的临床应用有限。我们试图测试替代的 DNA 回旋酶抑制剂的抗 NTM 活性。结核分枝杆菌回旋酶抑制剂（MGIs），是一类新型细菌拓扑异构酶抑制剂（NBTIs）的亚类，最近被证明对结核分枝杆菌具有活性。在这里，我们表明 MGI EC/11716 不仅具有很强的抗结核活性，而且对脓肿分枝杆菌和鸟分枝杆菌也有活性。我们专注于引起最难治疗的 NTM 疾病的脓肿分枝杆菌，表明 EC/11716 具有杀菌作用，对耐药生物膜有活性，并且在脓肿分枝杆菌肺部感染的小鼠模型中有效。基于耐药突变选择实验，我们报告了对 EC/11716 耐药的频率较低，并证实 DNA 回旋酶是其靶标。我们的研究结果表明，NBTIs 有潜力成为抗脓肿分枝杆菌和可能的广谱抗分枝杆菌药物。
