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A Purification and In Vitro Activity Assay for a pppGpp Synthetase from Clostridium difficile
Published on: November 3, 2018
In vitro activity of the novel antibacterial agent ibezapolstat (ACX-362E) against Clostridioides difficile
Beverly Murray1, Cindy Wolfe, Andrea Marra1
1Micromyx, Inc, 4717 Campus Drive, Kalamazoo, MI 49008, USA.
Background:
Ibezapolstat (ACX-362E) is the first DNA polymerase IIIC inhibitor undergoing clinical development for the oral treatment of Clostridioides difficile infection (CDI).
Methods:
In this study, the in vitro activity of ibezapolstat was evaluated against a panel of 104 isolates of C. difficile, including those with characterized ribotypes (e.g. 027 and 078) and those producing toxin A or B and was shown to have similar activity to those of comparators against these strains.
Results:
The overall MIC50/90 (mg/L) for ibezapolstat against evaluated C. difficile was 2/4, compared with 0.5/4 for metronidazole, 1/4 for vancomycin and 0.5/2 for fidaxomicin. In addition, the bactericidal activity of ibezapolstat was evaluated against actively growing C. difficile by determining the MBC against three C. difficile isolates. Time-kill kinetic assays were additionally performed against the three C. difficile isolates, with metronidazole and vancomycin as comparators.
Conclusions:
The killing of C. difficile by ibezapolstat was observed to occur at concentrations similar to its MIC, as demonstrated by MBC:MIC ratios and reflected in time-kill kinetic assays. This activity highlights the therapeutic potential of ibezapolstat for the treatment of CDI.
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