In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus.

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