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

Abstract

Candida albicansis 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 ofC. albicansresistance 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 planktonicC. albicanscells and inhibited biofilm formationin vitroandin vivo. Recent studies have suggested the use of antivirulence agents in combination with antifungals. In this study, we investigated the use of compounds that targetC. albicanspolymorphism, such as 1-dodecanol, isoamyl alcohol, and farnesol, to attempt to improve β-peptide efficacy for preventingC. albicansbiofilms. 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 preventingC. albicansbiofilm formation.

Various Biomimetics as Antifungals

“…One of the effective solutions to this problem today is the combined use of various antifungals. Such possible combinations can include various traditional antifungal agents and AFPs (Table 6) [18,37,45,57,67,[128][129][130][131][132][133][134][135][136][137][138][139][140]. Such combinations make it possible to joint different mechanisms (targets) of the effects of antifungals and significantly decrease their toxicity by improving the effectiveness of the action and reducing the doses applied in comparison with individual substances.…”

“…The hydrophobicity of the β-peptides directly correlates with their antifungal properties and a narrow range of concentrations at which β-peptides effectively kill C. albicans cells without lysis of erythrocytes. The combination of these peptides with isoamyl alcohol reduced their MIC for inhibiting biofilms by 4 times [138].…”

Cyclic Peptides with Antifungal Properties Derived from Bacteria, Fungi, Natural Products, and Synthetic Sources

“…To develop effective and specific antifungal compounds, Rodríguez López et al [67] conducted a study in which they designed amphiphilic, cationic, 14-helical β-peptides. These β-peptides were created to emulate the structural features of natural antimicrobial α-peptides and act as antifungal agents against planktonic C. albicans cells.…”

The Antimicrobial Peptide AMP-17 Derived from Musca domestica Inhibits Biofilm Formation and Eradicates Mature Biofilm in Candida albicans

“…According to the literature, the severity of C. albican biofilm has been linked to the increased cellular density associated with the biofilm community, C. albicans morphological changes such as yeast-hyphae transition, the protective effect of the extracellular matrix, and the production of drug efflux pumps [ 21 ]. Antifungal agents could play a crucial role in preventing and controlling biofilm-related infections if they target the aforementioned causes of biofilm formation.…”