In vitro characterization of the antibacterial spectrum of novel bacterial type II topoisomerase inhibitors of the aminobenzimidazole class
In vitro characterization of the antibacterial spectrum of novel bacterial type II topoisomerase inhibitors of the aminobenzimidazole class
复制标题
DOI：
10.1128/aac.50.4.1228-1237.2006
复制
发表时间：
2006-04-01
影响因子：
4.9
通讯作者：
Grossman, TH
中科院分区：
文献类型：
--
作者：
Mani, N;Gross, CH;Grossman, TH
具有新作用机制的抗生素在对抗细菌对目前使用的所有抗生素类别的耐药性方面正变得越来越重要。细菌DNA旋转酶和拓扑异构酶IV(TopoIV)是氟喹诺酮类和香豆素类抗生素常见的靶标。在这里，我们提出了一类新的合成细菌TopoII ATPase抑制剂的两个成员的特征：Vrt-125853和Vrt-752586。这些氨基苯并咪唑化合物是DNA旋转酶和TopoIV的有效抑制剂，对引起医院内和社区获得性感染的各种问题病原体具有良好的抗菌活性，包括葡萄球菌、链球菌、肠球菌和分枝杆菌。与其结构和作用机制的新颖性一致，抗菌效力不受常见的耐药表型的影响，包括氟喹诺酮耐药。在时间杀灭实验中，Vrt-125853和Vrt-752586对金黄色葡萄球菌、肺炎链球菌、粪肠球菌和流感嗜血杆菌均有杀菌作用，24 h内使活细胞数减少3个对数。最后，与氟喹诺酮类药物相似，它们对Vrt-125853和Vrt-752586的自发耐药率较低，这与它们的体外双靶向活性一致。
Antibiotics with novel mechanisms of action are becoming increasingly important in the battle against bacterial resistance to all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics. Here we present the characterization of two members of a new class of synthetic bacterial topoII ATPase inhibitors: VRT-125853 and VRT-752586. These aminobenzimidazole compounds were potent inhibitors of both DNA gyrase and topoIV and had excellent antibacterial activities against a wide spectrum of problematic pathogens responsible for both nosocomial and community-acquired infections, including staphylococci, streptococci, enterococci, and mycobacteria. Consistent with the novelty of their structures and mechanisms of action, antibacterial potency was unaffected by commonly encountered resistance phenotypes, including fluoroquinolone resistance. In time-kill assays, VRT-125853 and VRT-752586 were bactericidal against Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, and Haemophilus influenzae, causing 3-log reductions in viable cells within 24 h. Finally, similar to the fluoroquinolones, relatively low frequencies of spontaneous resistance to VRT-125853 and VRT-752586 were found, a property consistent with their in vitro dual-targeting activities.