Nystatin Action On POPC/sterol Membranes Along Its Phase Diagram

Abstract

Nystatin is a membrane active polyene antibiotic that has been studied for a long time due to its permeabilization activity. Its clinical use is based on the different potency in membranes containing ergosterol (fungi) vs membranes containing cholesterol (mammal). It has been proposed that the mechanism of permeabilization is through the formation of transmembrane pores constituted of several monomers of the drug in a barrel stave configuration. The greater selectivity in ergosterol containing membranes as compared with those containing cholesterol has been proposed to be due to greater pore stability produced by ergosterol. This hypothesis has been questioned over the time and alternative models have been suggested. Experimental evidence has shown that sterol is not a requirement for membrane permeabilization, then the proposal of an indirect role of sterol through the effect on membrane structure. This idea has been supported by experimental evidence showing a different action in different phases of the membrane. In order to evaluate the effect of phase changes of the membrane on the pores formed by Nystatin, single channel experiments were performed along the phase diagram of 1-palmitoyl-2-oleoyl-sn-glycero-phophocholine (POPC) membranes containing ergosterol (erg) or cholesterol (chol). The results show that for POPC-erg membranes there is a region of maximum permeabilization consistent with the liquid-ordered (lo) + liquid disordered (ld) mixed region. For the POPC-chol membranes the maximum permeabilization occurs also in the mixed region but at lower temperatures. These results are taken as strong evidence supporting the idea that the phase of the membrane is determinant for the activity of polyene antibiotics.