Location of the Positive Charges in Cationic Amphiphiles Modulates Their Mechanism of Action against Model Membranes

Abstract

Synthetic 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.

Amphiphilic Low-Molecular-Weight Gelators Bearing β-S-N-Acetylglucosamine Linked to a Tartaric Acid Scaffold: Synthesis, Self-Assembly and Wheat Germ Agglutinin Binding

“…Furthermore, these amphiphiles were able to bind to peanut agglutinin (PNA), a specific lectin that binds to lactose. Moreover, there are reports on the synthesis and properties of tartaric acid-derived Gemini-like and Bola-like amphiphiles, showing interesting properties as bactericides and antimicrobians [28,30]. Also, thermo-responsible chiral hydrogels were developed from catanionic surfactant mixtures made of diacyl-tartaric acids [31], as well as amphiphilic tartrate derivatives with transdermal permeation-enhancing activity of theophylline [32].…”

The Effect of an Intramembrane Light-Actuator on the Dynamics of Phospholipids in Model Membranes and Intact Cells

“…to evaluate possible effects on the integrity of the membrane and to elucidate the action mechanism. [5][6][7] Neutron scattering techniques, in particular, can be utilized effectively to investigate soft condensed matter, 8 owing to the abundance of hydrogen nuclei that strongly interact with neutrons. 9 Among these techniques, quasi-elastic neutron scattering (QENS) is well-suited to study molecular dynamics with timescales of ≈ 10 -13 -10 -9 s at length scales in the range of 1 -30 Å, 10,11 thus allowing to map out a wide range of motions, from fast vibrations to slower diffusions, at the level of intramolecular and intermolecular distances.…”

“…The ability of cationic amphiphiles to intercalate into the lipid membrane of eukaryotic and prokariotic cells has been largely exploited to modulate membrane physical properties, with the final goal of providing new pharmacological platforms for therapeutics, i.e., for the development of membrane-targeted antibiotic and antiviral drugs. − Cell membranes are complex two-dimensional fluids, whose dynamics can influence drug encapsulation and, vice versa, can be modified upon insertion of a guest molecule. Therefore, a detailed knowledge of the motions of phospholipids taking place at the molecular level is crucial for pharmacology, i.e., to evaluate possible effects on the integrity of the membrane and to elucidate the action mechanism. − Neutron scattering techniques, in particular, can be utilized effectively to investigate soft condensed matter, owing to the abundance of hydrogen nuclei that strongly interact with neutrons . Among these techniques, quasi-elastic neutron scattering (QENS) is well-suited to study molecular dynamics with timescales of ≈10 –13 –10 –9 s at length scales in the range of 1–30 Å, , thus allowing to map out a wide range of motions, from fast vibrations to slower diffusions, at the level of intramolecular and intermolecular distances .…”