Multimodal Membrane Poration by Thanatin

Antimicrobial resistance has motivated the search for antimicrobial agents with multimodal mechanisms of action. Host defense peptides and bacteriocins hold particular promise in this regard. Among many molecules discovered to date, thanatin appears to represent the properties of the two classes in that it, like bacteriocins, adopts a highly stable fold in solution and, like host defense peptides, exhibits broad-spectrum antibiotic activity. The peptide is believed to depolarize bacterial outer membranes and inhibit lipopolysaccharide transport while restoring bacterial susceptibility to β-lactam antibiotics. However, a direct observation of whether and how thanatin affects membranes is lacking. Here we reason that the peptide should promote bacteriocin-like multimodal poration in phospholipid bilayers. We demonstrate that thanatin induces poration with elements of membrane thinning, fractal ruptures, and transmembrane channels, a phenomenon common for bacteriocin folds but atypical of antimicrobial peptides. The results offer mechanistic insight into the action of antimicrobial agents emerging from different molecular classes but with similar properties.