Discovery of\nNovel Coumarin Pleuromutilin Derivatives\nas Potent Anti-MRSA Agents

Treating\nmethicillin-resistant Staphylococcus\naureus (MRSA) infection remains one of the most difficult\nchallenges in\nclinical practice, primarily due to the resistance of MRSA to multiple\nantibiotics. Therefore, there is an urgent need to develop novel antibiotics\nwith high efficacy and low cross-resistance rates. In this study,\na series of novel pleuromutilin derivatives with coumarin structures\nwere synthesized and subsequently assessed for their biological activities.\nMost of these derivatives showed potent antimicrobial activity against\ndrug-resistant Gram-positive bacterial strains. Compound <b>14b</b> displayed particularly rapid bactericidal effects, slow resistance\ndevelopment, and low cytotoxicity. Moreover, it decreased bacterial\nloads in the lung, liver, kidney, spleen, and heart and exhibited\nbetter antibacterial efficacy (ED<sub>50</sub> = 11.16 mg/kg) than\ntiamulin (ED<sub>50</sub> = 28.93 mg/kg) in a mouse model of systemic\nMRSA infection. Both in vitro and in vivo analyses suggest that compound <b>14b</b> is a promising agent for the treatment of MRSA infections.