Design, synthesis, and biological evaluation of novel pleuromutilin derivatives with methicillin-resistant Staphylococcus aureus -targeting phenol linker groups.

Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant global health threat, necessitating the development of new therapeutic agents. Pleuromutilin derivatives offer a promising solution due to their potent antibacterial activity, particularly against Gram-positive bacteria such as MRSA. In this study, we synthesized a series of pleuromutilin derivatives with phenol linker containing C14 side chains and evaluated in vitro and in vivo antibacterial activities. Several compounds showed potent activity against MRSA and Staphylococcus aureus with minimal inhibitory concentrations (MICs) as low as 0.03125 μg/mL. In particular, compounds a4 and b4 showed rapid bactericidal activity, significantly reducing MRSA loads in time-kill kinetics and exhibiting slower resistance development compared to tiamulin. In vivo, compound a4 showed superior efficacy in reducing MRSA-induced lung damage in a mouse model at a lower effective dose (ED50 = 6.48 mg/kg) compared to tiamulin (ED50 = 11.38 mg/kg). Molecular docking and molecular dynamics studies also showed that compound a4 binds strongly to the ribosomal peptidyl transferase center (PTC), a key target for pleuromutilin derivatives. These results suggest that compound a4, with its enhanced antibacterial activity and low resistance potential, is a promising candidate for further development as an effective treatment for MRSA infections.