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

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Infectious Diseases

Background:

• Mupirocin is a potent antibiotic limited to topical use due to rapid plasma degradation and short half-life.
• Enzymatic degradation in plasma restricts mupirocin's systemic therapeutic potential for bacterial infections.

Purpose of the Study:

• To design and synthesize mupirocin prodrugs to enhance pharmacokinetic properties for systemic delivery.
• To evaluate the efficacy of mupirocin prodrugs in preclinical models of bacterial infection.

Main Methods:

• Rational design of mupirocin prodrugs utilizing enzymatically cleavable ester linkers targeting the carboxylic acid.
• Synthesis via selective esterification with lipophilic moieties and characterization using NMR and HRMS.
• Pharmacokinetic evaluation and assessment of anti-bacterial efficacy in murine lung infection models.

Main Results:

• The lead prodrug, 3d (cholesterol-disulfide linker), exhibited a 6-fold increase in plasma half-life compared to mupirocin.
• Compound 3d demonstrated a 1356-fold greater pulmonary area under the concentration-time curve (AUC).
• 3d showed potent anti-methicillin-resistant Staphylococcus aureus (MRSA) efficacy in systemic and neutropenic murine lung infection models.

Conclusions:

• The prodrug strategy effectively overcomes mupirocin's pharmacokinetic limitations, enabling systemic application.
• Mupirocin prodrugs hold significant potential for treating systemic bacterial infections, particularly MRSA.
• This approach validates prodrug development for enhancing antibiotic systemic bioavailability and efficacy.