Sulfonium Modification of Echinocandins: An Effective Strategy to Combat Intrinsically Resistant Cryptococcus via Membrane Disruption and Enhanced Cell Wall Biosynthesis Inhibition

Abstract Fungal infections claim millions of lives annually and intrinsic resistance of Cryptococcus against echinocandins severely impedes clinical treatment. In this study, sulfonium covalent modification was performed based on natural pneumocandin B0 scaffold. The obtained derivatives exhibited potent activity against Candida species and reversed innate resistance of Cryptococcus neoformans, with MIC values reaching as low as 2 μg/mL. Structural modification elevated fungal membrane permeability and induced membrane depolarization, while enhancing the inhibitory effect on glucan synthase and disturbing cell wall biosynthesis. Compounds 3h and 5h possessed low drug resistance potential, favorable safety profiles, satisfactory pharmacokinetic properties and robust in vivo antifungal efficacy. This modification strategy facilitates the development of novel antifungal candidates.