Abstract
INTRODUCTION: LYSC98 is a novel vancomycin derivative used for gram-positive bacterial infections. Here we compared the antibacterial activity of LYSC98 with vancomycin and linezolid in vitro and in vivo. Besides, we also reported the pharmacokinetic/pharmacodynamic (PK/PD) index and efficacy-target values of LYSC98. METHODS: The MIC values of LYSC98 were identified through broth microdilution method. A mice sepsis model was established to investigate the protective effect of LYSC98 in vivo. Single-dose pharmacokinetics of LYSC98 was studied in thigh-infected mice and liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine LYSC98 concentration in plasma. Dose fractionation studies were performed to evaluate different PK/PD indices. Two methicillin-resistant Staphylococcus aureus (MRSA) clinical strains were used in the dose ranging studies to determine the efficacy-target values. RESULTS: LYSC98 showed a universal antibacterial effect in Staphylococcus aureus with a MIC range of 2-4 µg/mL. In vivo, LYSC98 demonstrated distinctive mortality protection in mice sepsis model with an ED(50) value of 0.41-1.86 mg/kg. The pharmacokinetics results displayed maximum plasma concentration (C(max)) 11,466.67-48,866.67 ng/mL, area under the concentration-time curve from 0 to 24 h (AUC(0-24)) 14,788.42-91,885.93 ng/mL·h, and elimination half-life (T(1/2)) 1.70-2.64 h, respectively. C(max)/MIC (R (2) 0.8941) was proved to be the most suitable PK/PD index for LYSC98 to predict its antibacterial efficacy. The magnitude of LYSC98 C(max)/MIC associated with net stasis, 1, 2, 3 and 4 - log (10) kill were 5.78, 8.17, 11.14, 15.85 and 30.58, respectively. CONCLUSION: Our study demonstrates that LYSC98 is more effective than vancomycin either in killing vancomycin-resistant Staphylococcus aureus (VRSA) in vitro or treating S. aureus infections in vivo, making it a novel and promising antibiotic. The PK/PD analysis will also contribute to the LYSC98 Phase I dose design.