Recent Advances in Pleuromutilin Derivatives as Antimicrobial Agents (2015–2025)

Pleuromutilin is a natural product with promising therapeutic potential and important applications for antimicrobial drug development. The semisynthetic pleuromutilin derivatives obtained through structural modification of the C-14 side chain exhibit significantly enhanced antibacterial activity and pharmacokinetic properties. These compounds specifically bind to the peptidyl transferase center of the bacterial 50S ribosomal subunit to inhibit protein synthesis. To date, pleuromutilin derivatives have shown efficacy against drug-resistant Gram-positive bacteria, some Gram-negative bacteria, and <i>Mycoplasma</i>. This Perspective systematically summarizes research advances in the structural modification and antibacterial activity of pleuromutilin derivatives, with a focus on breakthrough achievements in enhancing antibacterial potency through innovative side-chain designs from 2015 to 2025. Furthermore, this study highlights future directions for innovative drug development based on pleuromutilin structural modification, offering insights into addressing the global challenge of antibiotic resistance.