Discovery of novel triphenylphosphonium conjugated pleuromutilin with enhanced anti-MRSA effect and broaden antibacterial spectrum.

Pleuromutilin, a diterpene fungal metabolite, serves as a privileged scaffold for antibiotic discovery. Improving its antibacterial activity and broadening its spectrum remain the primary objectives in developing novel pleuromutilin derivatives. To obtain an ideal candidate, a series of pleuromutilin analogues conjugated to the triphenylphosphonium cation (TPP+) were designed and synthesized. Among them, compound a5 demonstrated enhanced anti-MRSA potency and a broadened antibacterial spectrum compared to valnemulin and lefamulin, both in vitro and in vivo. Mechanistic studies revealed that a5 disrupted bacterial membranes and biofilms by elevating intracellular ROS levels-a mechanism distincts from conventional pleuromutilins, which primarily target ribosomal proteins. These findings position a5 as a promising lead compound for developing next-generation broad-spectrum antibacterial agents.