Insights into the Mechanism of Inhibition of Novel Bacterial Topoisomerase Inhibitors from Characterization of Resistant Mutants of Staphylococcus aureus
Insights into the Mechanism of Inhibition of Novel Bacterial Topoisomerase Inhibitors from Characterization of Resistant Mutants of Staphylococcus aureus
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DOI：
10.1128/aac.00571-15
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发表时间：
2015-09-01
影响因子：
4.9
通讯作者：
Alm, Richard A.
中科院分区：
文献类型：
--
作者：
Lahiri, Sushmita D.;Kutschke, Amy;Alm, Richard A.
II型拓扑异构酶DNA回转酶和IV型拓扑异构酶是经临床验证的细菌靶点，它们催化DNA拓扑结构的调节，这对DNA复制、修复和十烷化至关重要。氟喹诺酮类药物会捕获拓扑异构酶- dna复合物，对氟喹诺酮类药物的耐药性不断增加，导致在发现这些靶点的新型抑制剂方面做出了重大努力。AZ6142是一类新型细菌拓扑异构酶抑制剂（NBTIs）的成员，它利用一种独特的机制来捕获蛋白质- dna复合物。AZ6142对革兰氏阳性菌，包括金黄色葡萄球菌、肺炎链球菌和化脓性链球菌有很强的活性。在本研究中，我们测定了金黄色葡萄球菌和肺炎葡萄球菌对AZ6142和其他具有代表性的NBTI化合物的耐药频率。金黄色葡萄球菌和金黄色葡萄球菌在4倍MIC下选择耐药突变体的频率为1.7 × 10（-8）
The type II topoisomerases DNA gyrase and topoisomerase IV are clinically validated bacterial targets that catalyze the modulation of DNA topology that is vital to DNA replication, repair, and decatenation. Increasing resistance to fluoroquinolones, which trap the topoisomerase-DNA complex, has led to significant efforts in the discovery of novel inhibitors of these targets. AZ6142 is a member of the class of novel bacterial topoisomerase inhibitors (NBTIs) that utilizes a distinct mechanism to trap the protein-DNA complex. AZ6142 has very potent activity against Gram-positive organisms, including Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. In this study, we determined the frequencies of resistance to AZ6142 and other representative NBTI compounds in S. aureus and S. pneumoniae. The frequencies of selection of resistant mutants at 4 x the MIC were 1.7 x 10(-8) for S. aureus and