Reshaping Echinocandin Antifungal Drugs to Circumvent Glucan Synthase Point Mutation-Mediated Resistance

Echinocandins are important antifungal drugs that inhibit the activity of the membrane-bound glucan synthase complex, which is responsible for the synthesis of the fungal cell wall β-(1,3)-glucan. Echinocandin resistance, linked to mutations in Fks, the catalytic subunit of the glucan synthase complex, is on the rise, particularly in Candida species, the most common human fungal pathogens. In this study, we used molecular docking experiments between echinocandins and the recently reported structure of Fks to propose a model in which these drugs form a ternary complex with the enzyme and membrane lipids. We then used site-selective reductive dehydration of alcohols to generate dehydroxylated echinocandin derivatives, which we evaluated against a panel of Candida strains constructed by introducing resistance-conferring mutations. We found that removing the hemiaminal alcohol that drives alterations in the three-dimensional structures of the echinocandin reduced their efficacy. Conversely, eliminating the benzylic alcohol of echinocandins enhanced their efficacy by up to two orders of magnitude, depending on the resistance-conferring mutation. Our findings provide valuable insights into how site-selective modifications of echinocandins can be used to combat resistance to these clinically important antifungal drugs.