Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana 1000, Slovenia.
Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged H-6726, Hungary.
J Med Chem. 2023 Mar 23;66(6):3968-3994. doi: 10.1021/acs.jmedchem.2c01905. Epub 2023 Mar 6.
A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive , and multidrug resistant (MDR) strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 μg/mL] and against the Gram-negatives and (best compound MICs: range, 1-4 μg/mL). Lead compound was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of in complex with GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of and showed potent antibacterial activity against over 100 MDR and non-MDR strains of and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of in a mouse model of vancomycin-intermediate thigh infection was also demonstrated.
我们开发了一系列新的双低纳摩尔苯并噻唑类细菌 DNA 回旋酶和拓扑异构酶 IV 的抑制剂。得到的化合物表现出极好的广谱抗菌活性，对革兰氏阳性菌和多重耐药（MDR）菌株（最佳化合物最小抑菌浓度（MICs）范围：<0.03125-0.25 μg/mL）和革兰氏阴性菌和（最佳化合物 MICs 范围：1-4 μg/mL）均有良好的抑制作用。先导化合物 具有良好的溶解性和血浆蛋白结合率、良好的代谢稳定性、对细菌拓扑异构酶的选择性，且无毒性问题。化合物 与 GyrB24 的复合物的晶体结构揭示了其在 ATP 结合位点的结合模式。对 和 的进一步研究表明，它们对超过 100 株耐甲氧西林金黄色葡萄球菌和其他几种革兰氏阳性和革兰氏阴性菌株的多重耐药和非多重耐药菌株具有很强的抗菌活性。最终，还在万古霉素中介金黄色葡萄球菌大腿感染的小鼠模型中证明了 的体内疗效。
