Micromyx, Inc, 4717 Campus Drive, Kalamazoo, MI 49008, USA.
J Antimicrob Chemother. 2020 Aug 1;75(8):2149-2155. doi: 10.1093/jac/dkaa134.
Ibezapolstat (ACX-362E) is the first DNA polymerase IIIC inhibitor undergoing clinical development for the oral treatment of Clostridioides difficile infection (CDI).
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.
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.
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.
Ibezapolstat（ACX-362E）是首个正在开发用于治疗艰难梭菌感染（CDI）的口服药物的 DNA 聚合酶 IIIIC 抑制剂。
在这项研究中，评估了 Ibezapolstat 对包括具有特征性核糖体分型（例如 027 和 078）和产生毒素 A 或 B 的 104 株艰难梭菌分离株的体外活性，其对这些菌株的活性与比较剂相似。
评估的艰难梭菌对 Ibezapolstat 的总体 MIC50/90（mg/L）为 2/4，而甲硝唑为 0.5/4，万古霉素为 1/4，非达霉素为 0.5/2。此外，通过确定针对三种艰难梭菌分离株的 MBC 来评估 Ibezapolstat 对生长中的艰难梭菌的杀菌活性。还针对三种艰难梭菌分离株进行了时间杀伤动力学测定，以甲硝唑和万古霉素作为对照。
MBC:MIC 比值和时间杀伤动力学测定表明，Ibezapolstat 对艰难梭菌的杀灭作用发生在与其 MIC 相似的浓度下。这种活性突出了 Ibezapolstat 治疗 CDI 的治疗潜力。
