In Vitro and In Vivo Antibacterial Activity, Toxicity and Resistance Analysis of Pleuromutilin Derivative Z33 Against Methicillin-Resistant

The novel pleuromutilin derivative, which showed excellent in vitro antibacterial activity against MRSA, 22-(2-(2-(4-((4-(4-nitrophenyl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)acetamido)phenyl)thioacety-l-yl-22-deoxypleuromutilin (), was synthesized and characterized in our previous work. In this study, the preliminary pharmacodynamics and safety of were further evaluated. In in vitro antibacterial activity assays, was found to be a potent bactericidal antibiotic against MRSA that induced dose-dependent growth inhibition and long-term post-antibiotic effect (PAE). The drug-resistance test demonstrated that possessed a narrow mutant selection window and lower propensities to select resistance than that of tiamulin. Cytochrome P450 (CYP450) inhibition assay determined that the inhibitory effect of was similar to that of tiamulin against the activity of CYP3A4, and was lower than that of tiamulin on the activity of CYP2E1. Toxicity determination showed that both and tiamulin displayed low cytotoxicity of RAW264.7 cells. Furthermore, was found to be a high-security compound with a 50% lethal dose (LD) above 5000 mg/kg in the acute oral toxicity test in mice. In an in vivo antibacterial activity test, displayed better therapeutic effectiveness than tiamulin in the neutropenic mouse thigh infection model. In summary, was worthy of further development as a highly effective and safe antibiotic agent against MRSA infection.