An inhibitor of FtsZ with potent and selective anti-staphylococcal activity
An inhibitor of FtsZ with potent and selective anti-staphylococcal activity
复制标题
DOI：
10.1126/science.1159961
复制
发表时间：
2008-09-19
期刊：
影响因子：
56.9
通讯作者：
Czaplewski, Lloyd G.
中科院分区：
文献类型：
--
作者：
Haydon, David J.;Stokes, Neil R.;Czaplewski, Lloyd G.
FtsZ是一种必需的细菌鸟苷三磷酸酶，也是哺乳动物β-微管蛋白的同系物，其聚合并组装成环以启动细胞分裂。我们已经创造了一类小的合成抗菌剂，例如PC 190723，它抑制FtsZ并阻止细胞分裂。PC 190723对葡萄球菌，包括耐甲氧西林和多重耐药金黄色葡萄球菌，具有有效和选择性的体外杀菌活性。PC 190723的推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。PC 190723在体内感染模型中是有效的，治愈了用致死剂量的S.金黄色。该数据验证了FtsZ作为抗菌干预的靶标，并鉴定了PC 190723适合优化为新的抗葡萄球菌疗法。
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.