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Henrik Strahl

Wednesday 14 December 2016 - Beyond membrane permeabilization:
Novel mode of action of a membrane targeting peptide based on membrane rigidification and lipid phase separation

Due to the easy accessibility for extracellular agents, the bacterial cytoplasmic membrane is a major target for antimicrobials such as membrane-targeting peptides. These natural or synthetic antimicrobial peptides represent a largely untapped reservoir of potentially promising antibacterial lead-compounds. Commonly, membrane-targeting antimicrobial peptides are assumed to unfold their antimicrobial properties either by permeabilizing the cytoplasmic membrane resulting in leakage of intracellular content, or by membrane depolarization causing cell de-energization. However, not all membrane targeting peptides with strong antimicrobial properties share this mechanism. The cyclic hexapeptide cWFW does not exert its bactericidal activity by membrane permeabilization. Instead, the partitioning of cWFW into the lipid bilayers leads to a rapid reduction of membrane fluidity both in live Bacillus subtilis cells and in model membranes.

This effect is accompanied by the formation of large lateral membrane domains which are characterized by a difference in local membrane fluidity. Importantly, the demixing of native phospholipids triggers segregation of peripheral and integral membrane proteins into separate domains. The domain formation thus not only results in changes in local lipid environment surrounding membrane proteins, but also causes spatial dissociation of membrane protein functions. One specific and essential cellular system disrupted by this process is the cell wall synthetic machinery. The inhibition of cell wall synthesis contributes to the rapid antimicrobial effect and ultimately leads to autolysis, a property which explains the bacteriolytic activity of cWFW. These findings demonstrate a surprising and novel mechanism of action for the cyclic hexapeptide cWFW based on reduction of membrane fluidity combined with phospholipid demixing which severely disrupts the general membrane organization. This complex mode of action holds a low risk to induce bacterial resistance, and provides valuable information for the design of novel synthetic AMPs.