Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection

A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 μg/mL). Furthermore, the result of time-kill curves showed that compound had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound (K = 1.77 × 10 M) showed stronger affinity to the 50S ribosome than tiamulin (K = 2.50 × 10 M). The antibacterial activity of compound was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log CFU/mL), and compound performed a treatment effect (~1.3 log CFU/mL). In addition, compound was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC = 2.92 μg/mL).