Evaluation of Platensimycin and Platensimycin-Inspired Thioether Analogues against Methicillin-Resistant Staphylococcus aureus in Topical and Systemic Infection Mouse Models

摘要

Staphylococcus aureus is one of the most common pathogens for hospital-acquired and community-acquired infections. Methicillin-resistant S. aureus (MRSA) formed biofilms in wounds are difficult to treat with conventional antibiotics. By targeting FabB/FabF of bacterial fatty acid synthases, platensimycin (PTM) was discovered as a promising natural antibiotic against MRSA infections. In this study, PTM and its previously synthesized sulfur-Michael derivative PTM->2t, could reduce over 95% biofilm formation from S. aureus ATCC 29213 when used at 2 μg/mL in vitro. Topical application of ointments containing PTM or PTM->2t (2 × 4 mg/day/mouse) was successfully used to treat MRSA infections in a BABL/c mouse wound burn model. As a potential prodrug lead, PTM->2t showed improved in vivo efficacy in a mouse peritonitis model, compared to PTM. Our study suggests that PTM and its analogue may be used topically or locally to treat bacterial infections. In addition, the use of prodrug strategies might be instrumental to improve the poor pharmacokinetics properties of PTM.