Membrane Disruption

Membrane disruption is a mechanism of action without a receptor. A cationic, amphipathic peptide partitions onto a bilayer, driven by charge and by burial of its hydrophobic face, then reorganises it once a threshold surface density is reached. Three idealised models describe what follows: barrel-stave pores, toroidal pores lined by lipid head groups, and a carpet model in which peptide solubilises the surface like a detergent. All end in loss of transmembrane potential and leakage of ions and metabolites.

Selectivity comes from lipid composition, not sequence recognition: bacterial membranes expose anionic phosphatidylglycerol and cardiolipin, while a mammalian outer leaflet is largely zwitterionic and stiffened by cholesterol. Approved drugs exploit this. Polymyxin B and colistin bind lipid A in the Gram-negative outer membrane; daptomycin inserts into Gram-positive membranes in a calcium-dependent way and depolarises them. Both carry the narrow margins the mechanism implies, colistin visibly through nephrotoxicity.

For a membrane-active peptide the meaningful number is a ratio, not a single potency. A minimum inhibitory concentration means little without the haemolytic concentration from the same laboratory, and the index between them decides whether a molecule is a systemic or topical candidate. The mechanism resists conventional resistance evolution, since there is no target protein to mutate.

The claim to distrust is a bare inhibitory concentration. A peptide reported to kill bacteria at low micromolar concentrations may lyse red cells in the same range, and research peptide documentation almost never includes a haemolysis assay. The second misuse is rhetorical: membrane disruption invoked to explain a systemic benefit, when a molecule permeabilising membranes non-selectively at those concentrations would be a toxin.