Hydrophobicity and Helicity Regulate the Antifungal Activity of 14-Helical β-Peptides

Abstract

Candida albicans is one of the most prevalent fungal pathogens, causing both mucosal candidiasis and invasive candidemia. Antimicrobial peptides (AMPs), part of the human innate immune system, have been shown to exhibit antifungal activity but have not been effective as pharmaceuticals because of low activity and selectivity in physiologically relevant environments. Nevertheless, studies on α-peptide AMPs have revealed key features that can be designed into more stable structures, such as the 14-helix of β-peptide-based oligomers. Here, we report on the ways in which two of those features, hydrophobicity and helicity, govern the activity and selectivity of 14-helical β-peptides against C. albicans and human red blood cells. Our results reveal both antifungal activity and hemolysis to correlate to hydrophobicity, with intermediate levels of hydrophobicity leading to high antifungal activity and high selectivity toward C. albicans. Helical structure-forming propensity further influenced this window of selective antifungal activity, with more stable helical structures eliciting specificity for C. albicans over a broader range of hydrophobicity. Our findings also reveal cooperativity between hydrophobicity and helicity in regulating antifungal activity and specificity. The results of this study provide critical insight into the ways in which hydrophobicity and helicity govern the activity and specificity of AMPs and identify criteria that may be useful for the design of potent and selective antifungal agents.

Antifungal activity of a β-peptide in synthetic urine media: Toward materials-based approaches to reducing catheter-associated urinary tract fungal infections

“…We sought to develop new approaches that exploit the specific advantages of AMPs using β-peptide-based mimics of AMPs designed to fold into helical structures that are more stable in complex and higher ionic strength media [28–30]. Past studies have shown that β-peptide mimics of anti-bacterial AMPs can be designed to exhibit potent and specific antifungal activities, and that they fold into helical structures that are not disrupted at physiological ionic strength (150 mM) [31–34]. This combination of features and properties renders β-peptide AMP mimics promising as candidates for preventing fungal infections in urinary catheters.…”

Incorporation of β-Amino Acids Enhances the Antifungal Activity and Selectivity of the Helical Antimicrobial Peptide Aurein 1.2

“…7 However, these peptidomimetic AMPs exhibit structural folding patterns that are distinct from those of natural AMPs, preventing conservation of side-chain presentation and often adversely influencing AMP interactions with target cell membranes. In prior work, we generated antifungal β-peptides that were structurally inspired by cationic, amphiphilic AMPs 9, 10 . While these β-peptides exhibit the global amphiphilicity of AMPs, the side chain organization around the 14-helix periphery differs from that of native antimicrobial α-peptides.…”

Synthetic antimicrobialβ‐peptide in dual‐treatment with fluconazole or ketoconazole enhances thein vitroinhibition of planktonic and biofilmCandida albicans

“…The dual treatment of β ‐peptide (ACHC‐ β 3hV‐ β 3hK), mixed with either Fluc or Keto, possessed an enhanced biological effect against the fungal pathogenic model C. albicans . Specifically, this study determined whether reduced amounts of agents were enough to obtain an equal or better biological activity, focusing on the β ‐peptide that has a narrower therapeutic range . From our results, the Keto+( β ‐peptide) mix demonstrated a more pronounced difference between the single and mixed treatments when compared with the Fluc+( β ‐peptide) treatment.…”