Effect of Sequence and Structural Properties on 14-Helical β-Peptide Activity against Candida albicans Planktonic Cells and Biofilms

Abstract

Beta-peptides (beta-amino acid oligomers) that mimic the amphiphilic, helical, and cationic properties of natural antimicrobial peptides have previously been shown to display antifungal activity against planktonic Candida albicans cells. Beta-peptides offer several advantages over conventional peptides composed of alpha-amino acid residues, including conformational stability, resistance to proteases, and activity at physiological salt concentrations. We examined sequence-activity relationships toward both planktonic C. albicans cells and C. albicans biofilms, and the results suggest a toxicity mechanism involving membrane disruption. A strategy for fluorescently labeling a beta-peptide without diminishing antifungal activity was devised; labeled beta-peptides penetrated the cell membrane and accumulated in the cytoplasm of both planktonic and biofilm-associated cells. The labeled beta-peptide was detected only in metabolically inactive cells, which suggests that beta-peptide entry is correlated with cell death. The presence of a beta-peptide at a concentration near the minimum inhibitory concentration completely prevented planktonic C. albicans cells from forming a biofilm, suggesting that beta-peptides may be useful in preventing fungal colonization and biofilm formation.

The antifungal effect of peptides from hymenoptera venom and their analogs

“…As far as activity is concerned, the synthetic alpha helical beta-peptides of ten amino acid residues described by Karlsson et al [32] are the most similar to our peptides. Their most active peptides showed MIC values of 8-16 µg/ml, i.e.…”

“…4-9 µM, and are described to be active also against the biofilm form of C. a. In preliminary experiments (using the same experimental conditions [32] for biofilm formation and incubation with a peptide), our peptides were similarly active (MIC of ~50 µM).…”

Peptidomimetics as Antimicrobial Agents

“…To assess the potential of antimicrobial peptoids as bioavailable antibiotics, the in vivo pharmacokinetics of peptoids was studied [52]. The 64 Cu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was conjugated to peptoids and the resulting compounds were analyzed by positron emission tomography (PET). It is interesting that the amphipathicity of peptoids significantly affects their biodistributions, implying the potential for the rational design of peptoids for the specific delivery of therapeutic agents to a specific tissue or organs [52].…”

The Development of Antimicrobial γ-Aapeptides

“…To circumvent those drawbacks, over last decade, non-natural peptidomimetics that mimic the globally amphipathic structures and mechanism of action of HDPs have been developed and investigated, such as β-peptides [17][18][19], peptoids [20][21][22][23][24], arylamide oligomers [25,26], β-turn mimetics [27,28] and others [29,30]. Recently, we developed a new class of peptidomimetics termed 'γ-AApeptides' [31,32].…”