Olefinic side chain modification of fusidic acid enhances anti-MRSA activity and mitigates resistance development.

The escalating prevalence of antibiotic resistance underscores the urgent need for innovative antimicrobial agents. Fusidic acid (FA), a fungal-derived tetracyclic triterpene clinically employed against methicillin-resistant (MRSA), is limited by rapid resistance development and elevated MIC values in resistant strains. While previous olefinic side chain (Δ) modifications yielded FA derivatives with retained anti-MRSA activity, most analogs exhibited compromised efficacy against Gram-positive bacteria. To address this limitation, we systematically engineered the olefinic side chain through Wittig and olefin metathesis reactions, synthesizing 26 novel FA derivatives. Compound 10a emerged as a standout candidate, demonstrating MIC value lower than FA against MRSA (0.125 μg mL) as well as low resistance. It also exhibited biofilm disruption capability of reducing MRSA biofilm formation by 61.4% at 0.5 × MIC, along with downregulation of biofilm-related regulators (, ). In a murine skin infection model, compound 10a significantly inhibited bacterial growth and accelerated wound healing at 2 mg kg. Given these advantages, compound 10a represents a promising candidate molecule for combating multidrug-resistant Gram-positive infections.