Cardiolipin prevents pore formation in phosphatidylglycerol bacterial membrane models

Abstract

Several antimicrobial peptides, including magainin and the human cathelicidin LL‐37, act by forming pores in bacterial membranes. Bacteria such as Staphylococcus aureus modify their membrane's cardiolipin composition to resist such types of perturbations that compromise their membrane stability. Here, we used molecular dynamic simulations to quantify the role of cardiolipin on the formation of pores in simple bacterial‐like membrane models composed of phosphatidylglycerol and cardiolipin mixtures. Cardiolipin modified the structure and ordering of the lipid bilayer, making it less susceptible to mechanical changes. Accordingly, the free‐energy barrier for the formation of a transmembrane pore and its kinetic instability augmented by increasing the cardiolipin concentration. This is attributed to the unfavorable positioning of cardiolipin near the formed pore, due to its small polar head and bulky hydrophobic body. Overall, our study demonstrates how cardiolipin prevents membrane‐pore formation and this constitutes a plausible mechanism used by bacteria to act against stress perturbations and, thereby, gain resistance to antimicrobial agents.

Cardiolipin Strongly Inhibits the Leakage Activity of the Short Antimicrobial Peptide ATRA-1 in Comparison to LL-37, in Model Membranes Mimicking the Lipid Composition of Staphylococcus aureus

“…A recent molecular dynamics study showed that there is an increase in the free-energy cost of forming pores in saturated membranes (DMPG) in the liquid-crystalline state when the membranes contain CL. This increase in energy cost was attributed to the negative curvature of the molecule which augmented the curvature energy cost of pore formation by participating directly in the pore structure [ 35 ]. The inhibition of antimicrobial peptides because of the negative curvature of CL has also been discussed extensively elsewhere [ 36 , 37 , 38 ].…”

Small molecules enhance the potency of natural antimicrobial peptides

“…Real bacterial membranes have a highly variable composition, depending on species and environmental conditions ( 49 ) and realistic modeling of a specific membrane is beyond the scope of the current study. Future work could consider other important classes of lipid, such as cardiolipins ( 17 ), which have been implicated in resistance to AMP's ( 50 ), or models of asymmetric membranes ( 51 ).…”

Dendritic systems for bacterial outer membrane disruption as a method of overcoming bacterial multidrug resistance

“…The different percentage content of cardiolipin in membrane may affect the effectivness of many permeabilizers such as antimicrobial peptides. 45,46 Natural and synthetic permeabilizers of outer bacteria membrane Therefore, when searching for new alternatives to antibiotics, the permeabilization of the bacterial OM has to be taken into account. There has been an increase in papers describing antimicrobial properties of different permeabilizing agents, including natural (AMPs, antimicrobial proteins, e.g., Lysozyme or Gasdermin D) and synthetic agents, such as nanomaterials (including dendritic NPs).…”

“…The different percentage content of cardiolipin in membrane may affect the effectivness of many permeabilizers such as antimicrobial peptides. 45,46…”