Integration of Multiscale Molecular Modeling Approaches with the Design and Discovery of Fusidic Acid Derivatives

Abstract

<b>Aim:</b> Fusidic acid (FA) is an effective antibiotic against <i>Staphylococcus aureus</i>, but it is metabolically unstable. <b>Methods & results:</b> 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 <i>in vivo</i> 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. <b>Conclusion:</b> The results suggest that introducing groups that block the metabolic sites of FA could maintain antibacterial activity and prolong the half-lives.