Activity of AmB along a Phase Diagram Presenting Micro and Nanodomains

Abstract

Polyene antimicotics have been the most effective drug for more than five decades, and at the same time their mechanism of action is one of the most discussed biological processes. Understanding the molecular mode of action is essential not only for advancing our knowledge of transmembrane transport but also in the search for new derivatives with lower toxicity. Recently, two articles have stated that the mechanism of action of Amphotericine B has been resolved, proposing that the direct interaction of AmB with the sterols is responsible for selectivity towards fungal membranes (PNAS 1015023108, JACS 132,18266,2010). In our group, we have been advancing the idea that membrane structure is responsible for the drug selectivity, and two of our recent articles have demonstrated a strong correlation between the phase diagram of the lipidic membrane and the action of Nystatine (J. Memb. Biol. 2010,237,41-49 and 31-40). In order to continue the search for understanding the molecular mechanism of action, we performed an study of the activity of Amphotericine along a the phase diagram of ternary and quaternary mixtures of DSPC/DOPC/POPC/Chol that have shown to produce nano and microdomains in different parts of the phase diagram (Konyakhina et al., Biophy J, 101, L08-L10, 2011). We found again a strong correlation between membrane structure and polyene activity. Given the presence of different membrane domains, different levels of activity have been found in the formation of ionic channels with the patch-clamp technique.