Haydon David J, Stokes Neil R, Ure Rebecca, Galbraith Greta, Bennett James M, Brown David R, Baker Patrick J, Barynin Vladimir V, Rice David W, Sedelnikova Sveta E, Heal Jonathan R, Sheridan Joseph M, Aiwale Sachin T, Chauhan Pramod K, Srivastava Anil, Taneja Amit, Collins Ian, Errington Jeff, Czaplewski Lloyd G
Prolysis, Begbroke Science Park, Oxfordshire OX5 1PF, UK.
Science. 2008 Sep 19;321(5896):1673-5. doi: 10.1126/science.1159961.
FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian beta-tubulin that polymerizes and assembles into a ring to initiate cell division. We have created a class of small synthetic antibacterials, exemplified by PC190723, which inhibits FtsZ and prevents cell division. PC190723 has potent and selective in vitro bactericidal activity against staphylococci, including methicillin- and multi-drug-resistant Staphylococcus aureus. The putative inhibitor-binding site of PC190723 was mapped to a region of FtsZ that is analogous to the Taxol-binding site of tubulin. PC190723 was efficacious in an in vivo model of infection, curing mice infected with a lethal dose of S. aureus. The data validate FtsZ as a target for antibacterial intervention and identify PC190723 as suitable for optimization into a new anti-staphylococcal therapy.
FtsZ是一种必需的细菌鸟苷三磷酸酶，是哺乳动物β-微管蛋白的同源物，它会聚合并组装成一个环以启动细胞分裂。我们已经创建了一类小型合成抗菌剂，以PC190723为例，它可抑制FtsZ并阻止细胞分裂。PC190723对葡萄球菌具有强大且选择性的体外杀菌活性，包括耐甲氧西林和多重耐药的金黄色葡萄球菌。PC190723的假定抑制剂结合位点被定位到FtsZ的一个区域，该区域类似于微管蛋白的紫杉醇结合位点。PC190723在体内感染模型中有效，可治愈感染致死剂量金黄色葡萄球菌的小鼠。这些数据证实FtsZ是抗菌干预的一个靶点，并确定PC190723适合优化为一种新的抗葡萄球菌疗法。
