In Vitro and In Vivo Activity against Staphylococcus aureus and Pharmacokinetic Evaluation of a Novel Pleuromutilin Candidate.

Staphylococcus aureus infections pose a serious threat to public health, exacerbated by antimicrobial resistance and the limited pipeline of novel agents. Pleuromutilin, a natural antibiotic, provides a promising scaffold for developing new antibacterial agents via structural modification. To overcome the poor druggability of the lead compound amphenmulin (APM), we designed and synthesized a novel derivative, Pleuro2-4. This derivative exhibited potent in vitro activity against S. aureus, with efficacy comparable to valnemulin and superior to tiamulin. Molecular docking suggested favorable interactions with the bacterial ribosome, while scanning electron microscopy revealed morphological alterations associated with impaired cell division. Pharmacokinetics in mice revealed dose-dependent oral bioavailability (21.28% to 70.13%) and rapid metabolism to APM. Pleuro2-4 significantly reduced bacterial loads in a dose-dependent manner and alleviated histopathological damage in a neutropenic murine thigh infection model. Collectively, Pleuro2-4 exhibited improved oral exposure and bioavailability with potent antibacterial efficacy and favorable pharmacokinetic properties, warranting further pharmacokinetic/pharmacodynamic and efficacy studies in target species.