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

Aim: 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 2, inhibited the growth of Cryptococcus neoformans. Methods & results: Multiscale molecular modeling approaches were used to analyze the binding modes of 2 with eEF2. FA derivatives modified at the 3-OH position were designed based on in silico models; seven derivatives possessing different amino-terminal groups were synthesized and tested in vitro for antifungal activity against C. neoformans. Conclusion: Compound 7 had the strongest minimum inhibitory concentration. Two protonated nitrogen atoms of 7 interacted with a negative electrostatic pocket of eEF2 likely explain the superiority of 7-2. Graphical abstract