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

Feng B, Hu H, Xiang J, Wu G, Zhu Z, Zhang G, Zhang J, Pan W, Zhang W, Li T, Wu S

Eur J Med Chem 294 (-) 117731 [2025-09-15; online 2025-05-11]

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.

PubMed 40398156

DOI 10.1016/j.ejmech.2025.117731

Crossref 10.1016/j.ejmech.2025.117731

pii: S0223-5234(25)00496-9