title: Discovery and development of kibdelomycin, a new class of broad-spectrum antibiotics targeting the clinically proven bacterial type II topoisomerase.
abstract: 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.
authors.affiliation: SBS Pharma Consulting LLC, Edison, NJ 08820, United States. Electronic address: Sheo.Singh.215@gmail.com.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects* / Q000201:enzymology; D018360:Crystallography, X-Ray; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D011758:Pyrroles; D011760:Pyrrolidinones; D059005:Topoisomerase II Inhibitors; C000601708:kibdelomycin; D004250:DNA Topoisomerases, Type II
keywords: Antibacterials; Broad-spectrum; Clostridium difficile; DNA synthesis inhibitor; Gyrase inhibitor; Natural products; Novel target binding