Discovery and development of kibdelomycin, a new class of broad-spectrum antibiotics targeting the clinically proven bacterial type II topoisomerase

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• 作者：Sheo B. Singh ^{Sheo.Singh.215@gmail.com}
• 关键词：Antibacterials ; Natural products ; Gyrase inhibitor ; DNA synthesis inhibitor ; Novel target binding ; Broad-spectrum ; Clostridium difficile
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 December 2016
• 年：2016
• 卷：24
• 期：24
• 页码：6291-6297
• 全文大小：920 K
• 卷排序：24

文摘

Kibdelomycin is a complex novel antibiotic, discovered by applying a highly sophisticated chemical-genetic Staphylococcus aureus Fitness Test (SaFT) approach, that inhibits the clinically established bacterial targets, gyrase and topoisomerase IV. It exhibits broad-spectrum antibacterial activity against aerobic bacteria including MRSA and Acinetobacter baumannii. It is slowly bactericidal and has a low frequency of resistance. In an anaerobic environment, it exhibits narrow-spectrum activity and inhibits the growth of gut bacteria Clostridium difficile (MIC 0.125 μg/mL) without affecting the growth of commensal Gram-negative organisms particularly, Bacteroides sp. It is highly efficacious in the hamster model of C. difficile infection providing 100% protection at >6 mg/kg and 80% protection at 1.56 mg/kg by oral dosing without systemic exposure. X-ray co-crystal structures of kibdelomycin bound to GyrB and ParE showed a unique dual arm ‘U shaped’ multisite binding never encountered with any other gyrase inhibitors. Kibdelomycin is poised for preclinical development for C. difficile treatment, and most importantly, the co-crystal structures of kibdelomycin provide unique insight for structure-guided structure modification, which could lead to better broader-spectrum systemic antibiotic potentially covering many ESKAPE pathogens.