Interaction of surfactants based on 4,4'-bipyridine with bactericide potential with lipid bilayers by means of molecular dynamics simulations

• Grant number: 24/14657-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2024
• End date: March 31, 2026
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Physical-Chemistry
• Principal Investigator: Kalil Bernardino
• Grantee: Andrea Paravani da Costa
• Host Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil

Abstract

One of the major challenges in facing bacterial infections is the increasing emergence of bacteria that are resistant to conventional antibiotics, which makes it necessary to develop new types of drugs capable of combating them. In this context, ionic liquids have attracted great attention due to their unique physical properties and the possibility of synthesizing countless variations of ionic liquids through different combinations of cations and anions. With at least one of the species (usually the cation) having an amphiphilic character, a possible form of action as an antibiotic consists of the incorporation of this ion into the lipid bilayer of the bacteria, leading to structural changes and even to its rupture, inducing cell death. Although promising results have been obtained in recent years, with different ionic liquids being able to inhibit the growth of antibiotic-resistant bacteria even at very low concentrations, their mechanism of action is still not fully understood. Thus, this project aims to elucidate how ionic liquid-forming cations with bactericidal potential interact with bacterial lipid bilayers through classical molecular dynamics simulations. As a case study, ionic liquids with three cations of different geometries derived from 4,4'-bipyridine will be evaluated with the lipid bilayer of Pseudomas aeruginosa, a common bacterium in hospital infections in Brazil and resistant to most traditional antibiotics. Studies have shown that twin cations (2 heads and 2 tails) demonstrate greater potential for inhibition of this bacterium than traditional surfactant cations (1 head and 1 tail) or bicephalic cations (2 heads and 1 tail), an effect that is probably linked to differences in the cation geometry that, in turn, should affect its packing when incorporated into the bilayer. Equilibrium simulations will be performed to observe the spontaneous penetration of the three ionic liquids into the P. aeruginosa membrane, and calculations of the potential of mean force (pmf) will be performed to quantify the free energy of transfer of each of the cations from the aqueous solution to the interior of the bilayer. Based on the structures stored throughout the simulations, we will also evaluate changes that the respective cations induce in the lipid bilayer, such as changes in lipid packing, membrane thinning, or changes in its fluidity. These data should result in a rich description of the mechanism of action of these ionic liquids as bactericides, allowing the design of new structures that may be promising for applications such as antibiotics.