Activity of Amphotericin B on the Membrane Structure Presenting Macro, Modulated and Nano Domains in Mixtures of DSPC/DOPC/POPC/CHOL

Abstract

Polyenes antibiotics have been the most effective drug in the treatment of mycotic systemic infection for more than five decades, and at the same time, their mechanism of action has been a much discussed process. Understanding the molecular mode of action is essential not only for advancing our knowledge of trans-membrane transport, but also useful in the search for derivatives with lower collateral toxicity. In our group, we have been advancing the idea that membrane structure is responsible for drug selectivity of membranes with different sterol content. It has been shown that there is a strong correlation between the phase diagram of the lipid membrane and the action of Nystatin (J. Memb. Biol. 2010, 237, pages 41-49 and 31-40). Now we extend the study to consider the formation of ionic channels of Amphotericin B (AmB) in membranes containing ternary and quaternary mixtures of DSPC/DOPC/POPC/Chol, via tip-dip patch-clamp formation in their suspensions. These mixtures have been shown to produce Giant Unilamellar Vesicles (GUV's) with nano, modulated and macro domains in different regions of the phase diagram (Biophys. J, 2011, 101, L08-L10). The results show that there is a correlation between the particular phase that the mixture presents and the activity of AmB channels, both in conductance and kinetics. Since the phase diagram has been associated with the formation of different size domains we can see the effect of these, and particularly the ensuing interphases, on the formation and stability of the channels.