Basis For The Broad-spectrum Antimicrobial Activity Of Interfacially-active Peptides

Abstract

Recently, we rationally designed and screened a library of small, membrane pore-forming beta-strand peptides based on interfacial activity: “the ability of a molecule to partition into the membrane-water interface and to alter the packing and organization of lipids”. From this library we selected ten soluble and highly potent pore-forming peptides using a function based high-throughput screen. Many natural antimicrobial peptides (AMP) act directly on microbes and permeabilize their membranes. Our library peptides were rationally designed to disrupt membranes which were similar to those of microbial membranes. Accordingly, in vitro experiments showed that the selected peptides permeabilize live microbial cell membranes and all ten have potent, broad-spectrum activity against many different species bacteria and fungi. These potent, biologically-active peptides apparently undergo nonspecific interactions with membranes. Here we explore the basis for broad-spectrum antimicrobial which is a very poorly understood phenomenon. We find that many members of the library have potent activity against some microbes, however broad-spectrum against multiple classes of microbes is rare overall. Similarly, subtle changes in peptide structure propensity cause the loss of activity against some microbes, but not others. Comparison of structure-function relation of these peptides in lipid vesicles to their activity in biological membrane suggests that “interfacial activity” is the basis for biological activity. A very specific and narrow range of interfacial activity gives rise to broad-spectrum antimicrobial activity.