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. 2014;58(4):2387-92.
doi: 10.1128/AAC.00021-14. Epub 2014 Feb 10.

Kibdelomycin is a potent and selective agent against toxigenic Clostridium difficile

Lynn Miesel  1 , David W Hecht, James R Osmolski, Dale Gerding, Amy Flattery, Fangbiao Li, Jing Lan, Philip Lipari, Jon D Polishook, Lianzhu Liang, Jenny Liu, David B Olsen, Sheo B Singh
Affiliations

Kibdelomycin is a potent and selective agent against toxigenic Clostridium difficile

Lynn Miesel et al. Antimicrob Agents Chemother. 2014.

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.

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Figures

FIG 1
FIG 1
Chemical structure of kibdelomycin.
FIG 2
FIG 2
Cumulative MICs of kibdelomycin and comparators against C. difficile isolates (n = 168) (Table 1).
FIG 3
FIG 3
Efficacy of kibdelomycin and vancomycin in the hamster CDAD model. (A) Four-day survival of the lethal infection. (B) C. difficile counts in cecal contents recovered 4 days postinfection. LOD, lowest level of organism detection.
FIG 4
FIG 4
Plasma time-concentration profile of kibdelomycin at a 1-mg/kg intravenous dose in C57BL/6 mice (n = 2). Plasma levels after an oral dose of 2 mg/kg were below the level of detection (<10 nM).
FIG 5
FIG 5
Time-concentration profile of kibdelomycin given at 6.25 mg/kg oral dose in the cecum contents and plasma of uninfected hamsters (n = 3).
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