Kibdelomycin Is a Potent and Selective Agent against Toxigenic Clostridium difficile

Clostridium difficile is the causative agent ofC. 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 againstC. difficile and gastrointestinal anaerobic organisms. ToxigenicC. 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 toxigenicC. difficile (MIC90 = 0.25 μg/ml) and most Gram-positive aerobic organisms but had little activity againstBacteroides species (MIC50 > 32 μg/ml;n = 270). Potent anti-C. difficile activity was also observed in the hamster model ofC. difficile colitis. Dosing at 1.6 mg/kg (twice-daily oral dose) resulted in protection from a lethal infection and a 2-log reduction inC. difficile cecal counts. A 6.25-mg/kg twice-daily oral dose completely eliminated detectableC. 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.