Design, synthesis, and evaluation of mupirocin prodrugs restoring systemic efficacy against MRSA.

The promising antibiotic mupirocin suffers from rapid enzymatic degradation in plasma, characterized by an extremely short half-life, which strictly limits its use to topical applications. To overcome this pharmacokinetic limitation, we rationally designed mupirocin prodrugs targeting its carboxylic acid with enzymatically cleavable ester linkers. The synthesis was achieved through a selective esterification reaction of the mupirocin's carboxyl group with various lipophilic moieties. All newly synthesized prodrug candidates were fully characterized using 1H NMR, 13C NMR, and HRMS. The lead compound 3d, featuring a cholesterol-disulfide linker, demonstrated optimized pharmacokinetic properties with a 6-fold extended plasma half-life and a remarkable 1356-fold greater pulmonary area under the concentration-time curve (AUC) compared to mupirocin. In both systemic and neutropenic murine lung infection models, 3d exhibited potent anti-MRSA efficacy (50-100 mg/kg). This study validates the prodrug approach as a viable strategy to unlock the systemic therapeutic potential of mupirocin against bacterial infections.