Bilayer Permeabilization and the 'Sand-in-a-Gearbox' Mechanism for Membrane-Active Molecules: Which Is Which?

Fiche publication

Date publication

juillet 2026

Journal

Antibiotics (Basel, Switzerland)

Auteurs

Membres identifiés du Cancéropôle Est :
Pr BECHINGER Burkhard

Tous les auteurs :
Vaezi Z, Bortolotti A, Di Stefano C, Bonacorsi S, Santucci V, Carneri F, Aisenbrey C, Konai MM, Acharya Y, Venanzi M, Khosravi-Far R, Bechinger B, Haldar J, Stella L, Roversi D, Bocchinfuso G

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/42650666

Résumé

Antimicrobial peptides are promising agents for combating resistant infections. They exhibit bactericidal activity against a wide range of microbes, primarily by disrupting the permeability of the bacterial membrane and ultimately causing cell death. Effective bacterial killing requires a high number of membrane-bound peptide molecules. Therefore, it is conceivable that peptide accumulation on the membrane could also interfere with essential cellular processes by altering bilayer dynamics, a hypothesis referred to as the "sand-in-a-gearbox" model. We systematically investigated how membrane dynamics is affected by a set of well-characterized yet highly diverse peptides: the natural AMP magainin 2, the toxin melittin, the synthetic peptides LAH4 and Killer-FLIP, and small membrane-active peptidomimetics with bactericidal activity. These effects were examined using fluorescence spectroscopy techniques, by measuring anisotropy, generalized polarization, and excimer formation of specific probes inserted at different depths within the lipid bilayer. The activity of all compounds extends beyond membrane permeabilization, and the perturbation of membrane dynamics, often associated with the so-called "sand-in-a-gearbox" mechanism, is a common feature among all systems analyzed. The membrane-active compounds induced a stiffening of the phospholipid bilayer by reducing lipid lateral mobility and decreasing water penetration, at least on the nanosecond timescale accessible to fluorescence measurements. The concentration range in which this behavior occurred was the same for all compounds studied. This threshold is, generally, higher than that required for membrane permeabilization and reflects near-complete coverage of the bilayer surface.