Small-Molecule Morphogenesis Modulators Enhance the Ability of 14-Helical β-Peptides To Prevent Candida albicans Biofilm Formation

Candida albicans is an opportunistic fungal pathogen responsible for mucosal candidiasis and systemic candidemia in humans. Often, these infections are associated with the formation of drug-resistant biofilms on the surfaces of tissues or medical devices. Increased incidence of C. albicans resistance to current antifungals has heightened the need for new strategies to prevent or eliminate biofilm-related fungal infections. In prior studies, we designed 14-helical beta-peptides to mimic the structural properties of natural antimicrobial beta-peptides (AMPs) in an effort to develop active and selective antifungal compounds. These amphiphilic, cationic, helical beta-peptides exhibited antifungal activity against planktonic C. albicans cells and inhibited biofilm formation in vitro and in vivo. Recent studies have suggested the use of antivirulence agents in combination with antifungals. In this study, we investigated the use of compounds that target C. albicans polymorphism, such as 1-dodecanol, isoamyl alcohol, and farnesol, to attempt to improve beta-peptide efficacy for preventing C. albicans biofilms. Isoamyl alcohol, which prevents hyphal formation, reduced the minimum biofilm prevention concentrations (MBPCs) of beta-peptides by up to 128-fold. Combinations of isoamyl alcohol and antifungal beta-peptides resulted in less than 10% hemolysis at the antifungal MBPCs. Overall, our results suggest potential benefits of combination therapies comprised of morphogenesis modulators and antifungal AMP peptidomimetics for preventing C. albicans biofilm formation.