University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
Department of Medical Microbiology and Infection Control, Amsterdam UMC, Location VU Medical Center, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands.
Eur J Med Chem. 2024 Oct 5;276:116693. doi: 10.1016/j.ejmech.2024.116693. Epub 2024 Jul 19.
New 2-pyrrolamidobenzothiazole-based inhibitors of mycobacterial DNA gyrase were discovered. Among these, compounds 49 and 51, show excellent antibacterial activity against Mycobacterium tuberculosis and Mycobacterium abscessus with a notable preference for mycobacteria. Both compounds can penetrate infected macrophages and reduce intracellular M. tuberculosis load. Compound 51 is a potent inhibitor of DNA gyrase (M. tuberculosis DNA gyrase IC = 4.1 nM, Escherichia coli DNA gyrase IC of <10 nM), selective for bacterial topoisomerases. It displays low MIC values (M. tuberculosis: 0.63 μM; M. abscessus: 2.5 μM), showing specificity for mycobacteria, and no apparent toxicity. Compound 49 not only displays potent antimycobacterial activity (MIC values of 2.5 μM for M. tuberculosis and 0.63 μM for M. abscessus) and selectivity for mycobacteria but also exhibits favorable solubility (kinetic solubility = 55 μM) and plasma protein binding (with a fraction unbound of 2.9 % for human and 4.7 % for mouse). These findings underscore the potential of fine-tuning molecular properties to develop DNA gyrase B inhibitors that specifically target the mycobacterial chemical space, mitigating the risk of resistance development in non-target pathogens and minimizing harm to the microbiome.
新的 2-吡咯酰胺苯并噻唑类分枝杆菌 DNA 回旋酶抑制剂被发现。其中，化合物 49 和 51 对结核分枝杆菌和脓肿分枝杆菌表现出优异的抗菌活性，对分枝杆菌具有明显的偏好。这两种化合物都可以穿透感染的巨噬细胞并减少细胞内结核分枝杆菌的负荷。化合物 51 是一种有效的 DNA 回旋酶抑制剂（结核分枝杆菌 DNA 回旋酶 IC = 4.1 nM，大肠杆菌 DNA 回旋酶 IC 低于 10 nM），对细菌拓扑异构酶具有选择性。它显示出低 MIC 值（结核分枝杆菌：0.63 μM；脓肿分枝杆菌：2.5 μM），对分枝杆菌具有特异性，且没有明显的毒性。化合物 49 不仅具有强大的抗分枝杆菌活性（结核分枝杆菌的 MIC 值为 2.5 μM，脓肿分枝杆菌的 MIC 值为 0.63 μM）和分枝杆菌的选择性，而且还表现出良好的溶解度（动力学溶解度为 55 μM）和血浆蛋白结合率（人血浆的未结合分数为 2.9%，鼠血浆的未结合分数为 4.7%）。这些发现强调了精细调整分子特性以开发专门针对分枝杆菌化学空间的 DNA 回旋酶 B 抑制剂的潜力，从而降低了非靶标病原体产生耐药性的风险，并最大限度地减少了对微生物组的伤害。
