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

Abstract

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.