Integration of multiscale molecular modeling approaches with the design and discovery of fusidic acid derivatives.

Aim: Fusidic acid (FA) is an effective antibiotic against Staphylococcus aureus, but it is metabolically unstable. Methods & results: 14 derivatives were designed and synthesized by blocking the metabolic sites of FA (21-COOH and 3-OH) to maintain antibacterial activity and prolong the half-life. Six derivatives showed good antibacterial activity, and the pharmacokinetic experiments confirmed that two derivatives modified in 21-COOH released FA in vivo and showed longer half-lives than FA. Docking analysis and structure-activity relationships indicated that the 3-glycine derivatives with more hydrogen-bonding acceptor sites and positively charged surface areas were more likely to have good antibacterial activity. Conclusion: The results suggest that introducing groups that block the metabolic sites of FA could maintain antibacterial activity and prolong the half-lives.