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DS-2969b is a novel GyrB inhibitor that is currently under clinical development for the treatment ofClostridium difficile infection (CDI). In this study, thein vitro andin vivo activities of DS-2969b were evaluated. DS-2969b inhibited the supercoiling activity ofC. difficile DNA gyrase. DS-2969b showed potentin vitro activity againstC. difficile clinical isolates with a MIC90 of 0.06 μg/ml, which was 2-, 32-, and 16-fold lower than the MIC90 s of fidaxomicin, vancomycin, and metronidazole, respectively. DS-2969b did not select spontaneously resistant mutants of variousC. difficile strains at 4× MIC, and the frequency of resistance development was less than 4.8 × 10−9 . In a hamster CDI model, 5-day oral administration of DS-2969b conferred complete protection from recurrence and mortality at 0.3 mg/kg of body weight once a day, in contrast to a 50% survival rate with fidaxomicin at 3 mg/kg once a day and 0% with vancomycin at a 50-mg/kg/dose twice a day. Even a single oral administration of 1 mg/kg of DS-2969b in the CDI model exhibited 100% animal survival without recurrence. DS-2969b was also efficacious by 5-day subcutaneous administration in the CDI model. DS-2969b showed similar levels of fecal excretion after intravenous and oral administrations in rats. These data support further development of DS-2969b as a drug for oral and intravenous treatment of CDI.

In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, against Clostridium difficile