Benzylic Dehydroxylation of Echinocandin Antifungal DrugsRestores Efficacy against Resistance Conferred by Mutated GlucanSynthase

Each year, infections caused by fungal pathogensclaim the lives of about 1.6 million people and affect the health ofover a billion people worldwide. Among the most recentlydeveloped antifungal drugs are the echinocandins, which non-competitively inhibit beta-glucan synthase, a membrane-boundprotein complex that catalyzes the formation of the mainpolysaccharide component of the fungal cell wall. Resistance toechinocandins is conferred by mutations inFKSgenes, whichencode the catalytic subunit of the beta-glucan synthase complex.Here, we report that selective removal of the benzylic alcohol of thenonproteinogenic amino acid 3S,4S-dihydroxy-L-homotyrosine ofthe echinocandins anidulafungin and rezafungin, restored theirefficacy against a large panel of echinocandin-resistantCandidastrains. The dehydroxylated compounds did not significantly affectthe viability of human-derived cell culture lines. An analysis of the efficacy of the dehydroxylated echinocandins against resistantCandidastrains, which contain mutations in theFKS1 and/orFKS2 genes of the parental strains, identified amino acids of the Fksproteins that are likely to reside in proximity to theL-homotyrosine residue of the bound drug. This study describes thefirst exampleof a chemical modification strategy to restore the efficacy of echinocandin drugs, which have a critical place in the arsenal ofantifungal drugs, against resistant fungal pathogens.

Automated summary

Each year, fungal infections cause millions of deaths and affect billions of people worldwide. Echinocandins, a new class of antifungal drugs, inhibit the synthesis of fungal cell wall components. This study demonstrates the effectiveness of a chemical modification strategy to restore the efficacy of echinocandins against drug-resistant fungal pathogens.