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Location of the Positive Charges in Cationic Amphiphiles Modulates Their Mechanism of Action against Model Membranes
journal contribution
posted on 2019-10-17, 12:06 authored by Marcio
M. Almeida, Katia R. Perez, Allison Faig, Kathryn E. Uhrich, Karin A. RiskeSynthetic
cationic amphiphiles (CAms) with physicochemical properties
similar to antimicrobial peptides are promising molecules in the search
for alternative antibiotics to which pathogens cannot easily develop
resistance. Here, we investigate two types of CAms based on tartaric
acid and containing two hydrophobic chains (of 7 or 11 carbons) and
two positive charges, located either at the end of the acyl chains
(bola-like, B7 and B11) or at the tartaric acid backbone (gemini-like,
G7 and G11). The interaction of the CAms with biomimetic membrane
models (anionic and neutral liposomes) was studied with zeta potential
and dynamic light scattering measurements, isothermal titration calorimetry,
and a fluorescent-based leakage assay. We show that the type of molecule
determines the mechanism of action of the CAms. Gemini-like molecules
(G7 and G11) interact mainly via electrostatics (exothermic process)
and reside in the external vesicle leaflet, altering substantially
the vesicle surface potential but not causing significant membrane
lysis. On the other hand, the interaction of bola-like CAms (B7 and
B11) is endothermic and thus entropy-driven, and these molecules reach
both membrane leaflets and cause substantial membrane permeabilization,
likely after clustering of anionic lipids. The lytic ability is clearly
higher against anionic membranes as compared with neutral membranes.
Within each class of molecule, longer alkyl chains (i.e., B11 and
G11) exhibit higher affinity and lytic ability. Overall, the molecule
B11 exhibits a high potential as antimicrobial agent, since it has
a high membrane affinity and causes substantial membrane permeabilization.