Kibdelomycin Is a Potent and Selective Agent against Toxigenic Clostridium difficile

Abstract

dClostridium 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 (MIC 90 ‫؍‬ 0.25 g/ml) and most Gram-positive aerobic organisms but had little activity against Bacteroides species (MIC 50 > 32 g/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 M (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.

Kibdelomycin Is a Bactericidal Broad-Spectrum Aerobic Antibacterial Agent

“…It binds the GyrB and ParE enzymes in a unique U-shaped binding mode with multipoint contacts (12). Kibdelomycin selectively inhibited C. difficile without affecting many other anaerobic gut bacteria, including Bacteroides species (11). It shows potent bactericidal activity against S. aureus, although it is slower than fluoroquinolones (Fig.…”

“…Kibdelomycin A is a less potent inhibitor of S. aureus gyrase supercoiling (IC 50 , 400 nM) and topoisomerase IV catenation (ParE IC 50 , 5,000 nM) but has been shown to be a potent inhibitor of E. coli gyrase B ATPase activity (IC 50 , 9 nM) though a poor inhibitor of the E. coli ParE ATPase (IC 50 , 6,400 nM) (10). We reported that kibdelomycin is a selective and potent inhibitor of Clostridium difficile growth without significantly affecting anaerobic Gram-negative bacteria, including Bacteroides species (11). It showed potent in vivo activity against C. difficile infection without systemic exposure (11).…”

“…We reported that kibdelomycin is a selective and potent inhibitor of Clostridium difficile growth without significantly affecting anaerobic Gram-negative bacteria, including Bacteroides species (11). It showed potent in vivo activity against C. difficile infection without systemic exposure (11). We recently reported an X-ray crystal structure of kibdelomycin bound to S. aureus and E. coli GyrB and ParE (12).…”

DNA replication proteins as potential targets for antimicrobials in drug-resistant bacterial pathogens

“…The co-crystal structures of kibdelomycin bound to the N-terminal domains of S. aureus GyrB and ParE revealed a novel mode of ‘dual’ ATPase inhibition by blocking ATP binding and destabilizing GyrB/ParE subunit dimerization 77 . Kibdelomycin displays strong antimicrobial activities against predominantly Gram-positive bacteria, including MRSA and C. difficile 78 , 79 . The MIC 90 for C. difficile was 0.5 mg/L, similar to the novel therapeutic fidaxomicin, but more potent than metronidazole and vancomycin 78 .…”

A Review of Experimental and Off-Label Therapies for Clostridium difficile Infection

“…Encouraging results were obtained with it in a hamster model of CDI in terms of survival (80–100%), bacterial elimination (2- to 5-log reduction of C. difficile counts) and a practically absent enteral absorption [25]. Upcoming phase I human trials have not yet been announced.…”