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

Fusidic acid (FA) is an effective antibiotic against , but it is metabolically unstable.  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 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. The results suggest that introducing groups that block the metabolic sites of FA could maintain antibacterial activity and prolong the half-lives.