Switching Cytolytic Nanopores into Antimicrobial Fractal Ruptures by a Single Side Chain Mutation
Katharine Hammond, Flaviu Cipcigan, Kareem Al Nahas, Valeria Losasso, Helen Lewis, Jehangir Cama, Fausto Martelli, Patrick W. Simcock, Marcus Fletcher, Jascindra Ravi, Phillip J. Stansfeld, Stefano Pagliara, Bart W. Hoogenboom, Ulrich F. Keyser, Mark S.P. Sansom, Jason Crain, Maxim G. Ryadnov
Abstract
Disruption of cell membranes is a fundamental host defense response found in virtually all forms of life. The molecular mechanisms vary but generally lead to energetically favored circular nanopores. Here, we report an elaborate fractal rupture pattern induced by a single side-chain mutation in ultrashort (8-11-mers) helical peptides, which otherwise form transmembrane pores. In contrast to known mechanisms, this mode of membrane disruption is restricted to the upper leaflet of the bilayer where it exhibits propagating fronts of peptide-lipid interfaces that are strikingly similar to viscous instabilities in fluid flow. The two distinct disruption modes, pores and fractal patterns, are both strongly antimicrobial, but only the fractal rupture is nonhemolytic. The results offer wide implications for elucidating differential membrane targeting phenomena defined at the nanoscale.