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 ED₅₀ 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 (R² 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.
Keywords: LYSC98, vancomycin derivative, pharmacokinetics and pharmacodynamics, Staphylococcus aureus , murine thigh infection model