title: Kibdelomycin is a potent and selective agent against toxigenic Clostridium difficile.
abstract: Clostridium difficile is the causative agent of C. difficile-associated diarrhea (CDAD), with increased risk in elderly populations. Kibdelomycin, a novel natural-product inhibitor of type II topoisomerase enzymes, was evaluated for activity against C. difficile and gastrointestinal anaerobic organisms. Toxigenic C. difficile isolates (n=168) from U.S. hospitals and anaerobic Gram-positive and Gram-negative organisms (n=598) from Chicago-area hospitals were tested. Kibdelomycin showed potent activity against toxigenic C. difficile (MIC90=0.25 μg/ml) and most Gram-positive aerobic organisms but had little activity against Bacteroides species (MIC50>32 μg/ml; n=270). Potent anti-C. difficile activity was also observed in the hamster model of C. difficile colitis. Dosing at 1.6 mg/kg (twice-daily oral dose) resulted in protection from a lethal infection and a 2-log reduction in C. difficile cecal counts. A 6.25-mg/kg twice-daily oral dose completely eliminated detectable C. difficile counts in cecal contents. A single 6.25-mg/kg oral dose showed that cecal contents were exposed to the drug at >2 μM (eightfold higher than the MIC), with no significant plasma exposure. These findings support further exploration of kibdelomycin for development of an anti-C. difficile agent.
authors: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors: Lynn
authors: L
authors: Miesel
authors: David W
authors: DW
authors: Hecht
authors: James R
authors: JR
authors: Osmolski
authors: Dale
authors: D
authors: Gerding
authors: Amy
authors: A
authors: Flattery
authors: Fangbiao
authors: F
authors: Li
authors: Jing
authors: J
authors: Lan
authors: Philip
authors: P
authors: Lipari
authors: Jon D
authors: JD
authors: Polishook
authors: Lianzhu
authors: L
authors: Liang
authors: Jenny
authors: J
authors: Liu
authors: David B
authors: DB
authors: Olsen
authors: Sheo B
authors: SB
authors: Singh
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D016360:Clostridioides difficile / Q000187:drug effects*; D003015:Clostridium Infections / Q000188:drug therapy*; D006224:Cricetinae; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests
chemical_list: D000900:Anti-Bacterial Agents