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

Md Ashrafuzzaman

doi:10.3390/membranes11040247

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.

Highlights

Chemotherapy drugs (CDs) thiocolchicoside (TCC) and taxol have been found to induce ion pores inside lipid bilayer membranes [1,2]
The EP-recorded lipid bilayer currents induced by two CD candidate molecules TCC and taxol were recently published [1,2]
We have used gramicidin S (GS) concentrations that fall far below the minimum GS concentrations required for membrane permeabilization [9]

Summary

Introduction

Chemotherapy drugs (CDs) thiocolchicoside (TCC) and taxol have been found to induce ion pores inside lipid bilayer membranes [1,2]. These pores are predicted to be toroidal type [3,4]. A cationic cyclic decapeptide gramicidin S (GS) (Figure 1B) is known to induce defects in lipid membranes [9]. All of these induced pores or channels and defects disrupt the lipid bilayer’s electrical insulation properties and force the membrane to conduct currents instantaneously or over a period of time.

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Discussion

Conclusion