Effects of duramycin on cardiac voltage-gated ion channels

Abstract

The amphipathic peptide duramycin is in clinical development for the treatment of cystic fibrosis. It is deposited in cellular membranes where it binds to phosphatidylethanolamine. Duramycin may thereby change the biophysical membrane properties and perturb the function of ion channels. If so, in heart tissue, its application carries the risk to elicit cardiac arrhythmias. In fact, premature ventricular complexes were observed in the electrocardiogram during toxicological testing in dogs. To study the arrhythmogenic potential of duramycin, we investigated its effects on currents through voltage-gated hERG potassium, sodium, and calcium channels in native cells, and using a heterologous expression system, by means of the whole-cell patch clamp technique; duramycin bath concentrations between 1 nM and 0.1 microM did not generate any effects on these currents. Concentrations >or=0.3 microM, however, reduced the amplitudes of all investigated currents. Moreover, sodium current fast inactivation kinetics was slowed in the presence of duramycin. A further rise in duramycin bath concentration (>or=3.3 microM) induced a leak current consistent with pore formation. The reported effects of duramycin on ion channel function are likely to arise from a change in the biophysical properties of the membrane rather than from a specific interaction of the peptide with ion channel proteins. Under therapeutic conditions (i.e., administration via inhalation), duramycin plasma concentrations are below 0.5 nM. Thus, upon inhalation, duramycin has a large safety margin and is highly unlikely to elicit arrhythmias.

Phosphatidylethanolamine is externalized at the surface of microparticles

“…As cancer cells are known to shed MPs [22], MDA MP-rich supernatant was stained with Duramycin-biotin and fluorescently-labeled streptavidin (SA) and visualized using confocal microscopy (Fig. 1).…”

“…Duramycin is thought to be cytotoxic by inducing pore formation at a higher concentration [22]. Thus, to avoid any potential of hemolysis, erythrocytes were incubated with only 250nM duramycin-biotin for 2-3 minutes, gently centrifuged at 200x g , washed, stained with 62.5nM SA633 for an additional 2-3 minutes, gently centrifuged at 200x g washed and resuspended in PBS.…”

Are Bacteriocins Underexploited? NOVEL Applications for OLD Antimicrobials

“…These lantibiotics are able to interact strongly with the phosphatidylethanolamine in cell membranes at a 1:1 ratio, thereby changing the biophysical properties of the membrane that result in perturbed ion channel function [202][203][204][205]. Under therapeutic conditions, duramycin is unlikely to provoke cardiac arrhythmias [206]. In addition, cinnamycin possesses haemolytic activity and an immune-strengthening effect [207,208].…”

Lantibiotics produced by Actinobacteria and their potential applications (a review)

“…In fact, it is an indirect inhibition because the lantibiotics bind at a 1 : 1 ratio and with high affinity and exclusive specificity to the substrate of PLA 2 , the phosphatidylethanolamine (PE) [21,83]. This binding alters the operation of ion channels [84][85][86], a feature that is exploited by the pharmaceutical industry for cystic fibrosis treatment, as discussed below [87,88]. Furthermore, as PLA 2 provides arachidonic acid, by releasing this fatty acid from phospholipids in the cell membranes to the enzymes responsible for the synthesis of eicosanoids, which are associated with inflammation, such lantibiotics can also be used in regulation of inflammatory processes [19,89].…”