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

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 24; pp. 6291 - 6297
• Main Author: Singh, Sheo B.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.12.2016
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterials; Broad-spectrum; Clostridium difficile; Clostridium difficile - drug effects; Clostridium difficile - enzymology; Crystallography, X-Ray; DNA synthesis inhibitor; DNA Topoisomerases, Type II - metabolism; Dose-Response Relationship, Drug; Drug Discovery; Gyrase inhibitor; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Natural products; Novel target binding; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrrolidinones - chemical synthesis; Pyrrolidinones - chemistry; Pyrrolidinones - pharmacology; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; DNA synthesis inhibitor; Antibacterials; Natural products; Novel target binding; Clostridium difficile; Gyrase inhibitor; Broad-spectrum
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.04.043

[Display omitted] 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 0.125μg/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 >6mg/kg and 80% protection at 1.56mg/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.