In vitro and in vivo antibacterial activity, resistance analysis and molecular docking study of pleuromutilin derivatives against Streptococcus suis.

This article focuses on evaluating the antimicrobial activity of 268 pleuromutilin derivatives modified at the C14 side-chain against Streptococcus suis, a zoonotic pathogen with rising antibiotic resistance. Among these derivatives, five (B43, B49, B52, B53, and B54) demonstrated superior in vitro antibacterial efficacy compared to the reference drug tiamulin, with B49 showing the most promising in vivo results by improving survival rates in mouse infection models. Safety assessments indicated low cytotoxicity and haemolytic toxicity for these derivatives, while resistance induction assays revealed comparable resistance potential to tiamulin for all except B43. Molecular docking and scanning electron microscopy studies suggested that B49 binds strongly to the 50S ribosomal subunit and disrupts bacterial cell membranes, supporting its potential as a candidate for further antimicrobial drug development against S. suis infections.