In vitro and in vivo activities of DS-2969b, a novel GyrB inhibitor, against Clostridium difficile [PublishAheadOfPrint]

DS-2969b is a novel GyrB inhibitor, which is currently under clinical development for treatment of Clostridium difficile infection (CDI). In this study, the in vitro and in vivo activities of DS-2969b were evaluated. DS-2969b inhibited the supercoiling activity of C. difficile DNA gyrase. DS-2969b showed potent in vitro activity against C. difficile clinical isolates with an MIC₉₀ of 0.06 μg/mL, which was 2-, 32-, and 16-fold lower than the MIC₉₀ of fidaxomicin, vancomycin, and metronidazole, respectively. DS-2969b did not select spontaneous resistant mutant of various C. difficile strains at 4 x MICs and the frequency of resistance development was less than 4.8 x 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 once a day compared with 50% survival rate with fidaxomicin at 3 mg/kg once a day and 0% with vancomycin at 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 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.

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