Synthesis, antifungal activity and potential mechanism of fusidic acid derivatives possessing amino-terminal groups.

Fusidic acid (FA) is a narrow-spectrum bacteriostatic antibiotic. We inadvertently discovered that a FA derivative modified by an amino-terminal group at the 3-OH position, namely , inhibited the growth of . Multiscale molecular modeling approaches were used to analyze the binding modes of with eEF2. FA derivatives modified at the 3-OH position were designed based on models; seven derivatives possessing different amino-terminal groups were synthesized and tested for antifungal activity against . Compound had the strongest minimum inhibitory concentration. Two protonated nitrogen atoms of interacted with a negative electrostatic pocket of eEF2 likely explain the superiority of -.