Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, P. R. China.
J Chem Inf Model. 2013 Aug 26;53(8):2131-40. doi: 10.1021/ci400203f. Epub 2013 Jul 25.
The Filamenting temperature-sensitive mutant Z (FtsZ), an essential GTPase in bacterial cell division, is highly conserved among Gram-positive and Gram-negative bacteria and thus considered an attractive target to treat antibiotic-resistant bacterial infections. In this study, a new class of FtsZ inhibitors bearing the pyrimidine-quinuclidine scaffold was identified from structure-based virtual screening of natural product libraries. Iterative rounds of in silico studies and biological evaluation established the preliminary structure-activity relationships of the new compounds. Potent FtsZ inhibitors with low micromolar IC₅₀ and antibacterial activity against S. aureus and E. coli were found. These findings support the use of virtual screening and structure-based design for the rational development of new antibacterial agents with innovative mechanisms of action.
丝状温度敏感突变体 Z（FtsZ）是细菌细胞分裂中一种必需的 GTPase，在革兰氏阳性菌和革兰氏阴性菌中高度保守，因此被认为是治疗抗生素耐药性细菌感染的有吸引力的靶标。在这项研究中，从天然产物库的基于结构的虚拟筛选中鉴定出了一类具有嘧啶-喹诺利定骨架的新型 FtsZ 抑制剂。通过反复的计算机研究和生物评价，确定了新化合物的初步结构-活性关系。发现了具有低微摩尔 IC₅₀ 的强效 FtsZ 抑制剂，对金黄色葡萄球菌和大肠杆菌具有抗菌活性。这些发现支持使用虚拟筛选和基于结构的设计来合理开发具有创新作用机制的新型抗菌剂。
