In vitro and in vivo activities of DS-2969b, a novel GyrB inhibitor, and its water-soluble prodrug, DS11960558, against methicillin-resistant Staphylococcus aureus [PublishAheadOfPrint]

DS-2969b is a novel GyrB inhibitor under clinical development. In this study, the in vitro activity of DS-2969b and in vivo activities of DS-2969b and its water-soluble prodrug, DS11960558, against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. DS-2969b inhibited the supercoiling activity of S. aureus DNA gyrase and the decatenation activity of its topoisomerase IV. DS-2969b showed antibacterial activity against Gram-positive aerobes but not against Gram-negative aerobes, except Moraxella catarrhalis and Haemophilus influenzae. DS-2969b was active against MRSA with an MIC₉₀ of 0.25 μg/mL, which was 8-fold lower than that of linezolid. The presence of a pulmonary surfactant did not affect the MIC of DS-2969b. DS-2969b showed time-dependent slow killing against MRSA. The frequency of spontaneous resistance was less than 6.2 x 10^-10 in all four S. aureus isolates at 4x MIC of DS-2969b. In a neutropenic MRSA-induced murine muscle infection model, DS-2969b was more efficacious than linezolid by both subcutaneous and oral routes. DS-2969b and DS11960558 showed efficacy in a neutropenic murine MRSA lung infection model. Pharmacokinetics and pharmacodynamics of DS-2969b and DS11960558 against MRSA were characterized in a neutropenic murine thigh infection model; time above MIC of free drug (f T_MIC) correlated best with in vivo efficacy, and static %f T_MIC was 43—49%. Sufficient f T_MIC was observed in the oral phase 1 multiple-ascending dose study of DS-2969b at 400 mg once a day. These results suggest that DS11960558 and DS-2969b have potential for intravenous-to-oral step-down therapy for treating MRSA infections with higher efficacy than linezolid.

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