Inhibition of Bacterial Toxin Activity using Receptor-Based Peptides

Abstract

For decades, researchers have been trying to elucidate critical determinants of the pathogenicity of human fungi. Only recently, has an international consortium of scientists succeeded in identifying such a factor-a peptide toxin secreted by the clinically important fungus Candida albicans. This peptide Candidalysin plays a crucial role during fungal infections of human mucosae. The peptide's virulence manifests in the direct damage of epithelial membranes, in the stimulation of a danger response signaling pathway and in the activation of epithelial immunity. We provided the first insights into the direct interaction between Candidalysin and lipid membranes [1]. The peptide's amphiphilic alpha-helical structure is described as a prerequisite for its binding to lipid membranes. In consequence of the initialized binding, the peptide inserts between the lipid head groups and aligns parallel to the bilayer surface. Upon increasing surface accumulation, however, the helix starts to penetrate the bilayer with oblique inclination. As a result, the bilayer is destabilized and transient local collapses occur. This carpet-like disintegration eventually leads to the disruption of the entire membrane. A comparison of host, bacterial and fungal model membranes will be used as an approach for understanding the selectivity of Candidalysin for non-self membranes. The influence of peptide aggregation and of C-terminal truncation on the mode of action of Candidalysin will be discussed.