The Antimicrobial Peptide Gramicidin S Enhances Membrane Adsorption and Ion Pore Formation Potency of Chemotherapy Drugs in Lipid Bilayers

Abstract

We recently published two novel findings where we found the chemotherapy drugs (CDs) thiocolchicoside (TCC) and taxol to induce toroidal type ion pores and the antimicrobial peptide gramicidin S (GS) to induce transient defects in model membranes. Both CD pores and GS defects were induced under the influence of an applied transmembrane potential (≈100 mV), which was inspected using the electrophysiology record of membrane currents (ERMCs). In this article, I address the regulation of the membrane adsorption and pore formation of CDs due to GS-induced possible alterations of lipid bilayer physical properties. In ERMCs, low micromolar (≥1 μM) GS concentrations in the aqueous phase were found to cause an induction of defects in lipid bilayers, but nanomolar (nM) concentration GS did nothing. For the binary presence of CDs and GS in the membrane-bathing aqueous phase, the TCC pore formation potency is found to increase considerably due to nM concentration GS in buffer. This novel result resembles our recently reported finding that due to the binary aqueous presence of two AMPs (gramicidin A or alamethicin and GS), the pore or defect-forming potency of either AMP increases considerably. To reveal the underlying molecular mechanisms, the influence of GS (0–400 nM) on the quantitative liposome (membrane) adsorption of CD molecules, colchicine and TCC, was tested. I used the recently patented direct detection method, which helps detect the membrane active agents directly at the membrane in the mole fraction relative to its concentrations in aqueous phase. We find that GS, at concentrations known to do nothing to the lipid bilayer electrical barrier properties in ERMCs, increases the membrane adsorption (membrane uptake) of CDs considerably. This phenomenological finding along with the GS effects on CD-induced membrane conductance increase helps predict an important conclusion. The binary presence of AMPs alongside CDs in the lipid membrane vicinity may work toward enhancing the physical adsorption and pore formation potency of CDs in lipid bilayers. This may help understand why CDs cause considerable cytotoxicity.

WMR Peptide as Antifungal and Antibiofilm against Albicans and Non-Albicans Candida Species: Shreds of Evidence on the Mechanism of Action

“…AMPs are 12-50 amino acid long peptides that have been discovered in all forms of life, including bacteria, vertebrates, and invertebrate species [9,10,[13][14][15]. Based on their physicochemical properties, they likely have a direct activity on the membrane bilayer [16,17], although sometimes they also have an intracellular target. AMPs are generally cationic and amphipathic; their net positive charge enhances electrostatic interactions with anionic bacterial membranes, while the amphipathic structure leads to membrane insertion, destabilization and disruption.…”

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…In a similar spirit, the use of conjugated antioxidants with antiretroviral drugs has been proposed to increase drug penetration into the central nervous system [599]. Additionally, peptides, including antimicrobial peptides, were proposed as an effective enhancer [600,601]. Recent MD simulations demonstrated that glycyrrhizic acid enhanced the translocation of the antiparasitic drug praziquantel through a lipid bilayer by lowering the free energy barrier associated with the hydrophobic center of the membrane along with a rearrangement of the lipid headgroups [252].…”

Cell Surface Binding and Lipid Interactions behind Chemotherapy-Drug-Induced Ion Pore Formation in Membranes

“…The general drug adsorption is tested in experiments on liposomes without and with the effects of cholesterol. Modest modulation in drug adsorption has been found due to cholesterol (which naturally promotes bilayer plasticity) unlike the enhancement in drug adsorption observed recently due to bilayer physical property modulating (bilayer elasticity promoting) amphiphiles capsaicin and triton X-100 [ 51 ] and small cyclic decapeptide gramicidin S [ 52 ] in vitro constructed lipid bilayer or liposome systems.…”