The Gram-positive obligate anaerobic spore-forming bacterium Clostridioides difficile is a nosocomial pathogen. The severity and prevalence of C. difficile infection (CDI) have caused the CDC to identify C. difficile as an ‘urgent threat’ and thus an infection control priority. Epidemic outbreaks of C. difficile diarrhoea are related to the expression of two protein exotoxins, TcdA and TcdB. They cause colitis in susceptible individuals. Production of these toxins results in a host response leading to severe diarrhoea, inflammation and tissue necrosis and the subsequent neutrophilic colitis and loss of intestinal barrier function through inactivation of Rho GTPases. In this study, Ibezapolstat is a first-in-class dichlorobenzyl purine analogue. It also has a unique mechanism of action that binds to and inhibits DNA polymerase IIIC (DNA pol IIIC) from aerobic, low G + C Gram-positive bacteria. it directly inhibits the DNA pol IIIC from C. difficile, with a Ki of 0.325 μM.
DNA pol IIIC is essential for replicative DNA synthesis in Gram-positive bacteria with a low G + C content. Ibezapolstat is related to the class of compounds exemplified by 6-anilinouracils (AUs) and 2-phenylguanines (PGs), analogues of 2′-deoxyguanosine 5′-triphosphate (dGTP). Moreover, Ibezapolstat displays antibacterial activities against a broad spectrum of C. difficile pathogens. It shows a MIC range of 1-8 μg/mL for a panel of 104 clinical isolates of C. difficile. In addition, Ibezapolstat is poorly absorbed and apparently nontoxic in the hamster C. difficile-associated disease.
In summary, Ibezapolstat is a first-in-class, orally active DNA polymerase IIIC (pol IIIC) inhibitor. The Ki is 0.325 μM for the DNA pol IIIC from C. difficile. Thus, Ibezapolstat has the potential for the research of C. difficile infection (CDI).