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

Abstract

<i>Candida albicans</i> 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 <i>C. albicans</i> 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 β-peptides to mimic the structural properties of natural antimicrobial α-peptides (AMPs) in an effort to develop active and selective antifungal compounds. These amphiphilic, cationic, helical β-peptides exhibited antifungal activity against planktonic <i>C. albicans</i> cells and inhibited biofilm formation <i>in vitro</i> and <i>in vivo</i> Recent studies have suggested the use of antivirulence agents in combination with antifungals. In this study, we investigated the use of compounds that target <i>C. albicans</i> polymorphism, such as 1-dodecanol, isoamyl alcohol, and farnesol, to attempt to improve β-peptide efficacy for preventing <i>C. albicans</i> biofilms. Isoamyl alcohol, which prevents hyphal formation, reduced the minimum biofilm prevention concentrations (MBPCs) of β-peptides by up to 128-fold. Combinations of isoamyl alcohol and antifungal β-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 <i>C. albicans</i> biofilm formation.