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Competitive Binding of Cholesterol and Ergosterol to the Polyene Antibiotic Nystatin. A Fluorescence Study

Liana Silva ^*, Ana Coutinho ^* , Alexander Fedorov ^* and Manuel Prieto ^*

^* CQFM, Instituto Superior Técnico, Lisbon, Portugal; and DQB, Bloco C8, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal

Correspondence: Address reprint requests to Manuel Prieto, Centro de Química-Física Molecular, Instituto Superior Técnico, 1049-001 Lisbon, Portugal. Tel.: 351-218419219; Fax: 351-218464455; E-mail: prieto{at}alfa.ist.utl.pt.

Competition studies between cholesterol and ergosterol were carried out to gain insight into the binding interactions between nystatin and these sterols. Lipid vesicles were prepared with mixtures of palmitoyloleoylphosphocholine/ergosterol/cholesterol, and both sterol molar ratio and total content were varied. The inhibitory effect of cholesterol toward the ergosterol ability to induce the formation of long-lived fluorescent antibiotic species was used to detect nystatin-cholesterol interactions. It was found that the key factor controlling nystatin photophysical properties in the ternary lipid mixtures was their ergosterol/cholesterol molar ratio and not their overall sterol content. Moreover, permeabilization studies showed that nystatin was able to form pores in all the mixed vesicles, but the initial rate of pore formation was also dependent on the ergosterol/cholesterol molar ratio. Our data show that ergosterol is displaced by competing cholesterol, indirectly confirming cholesterol's ability to coassemble with nystatin. The distinct spectroscopic properties emphasize the different molecular architecture adopted by nystatin-cholesterol and -ergosterol complexes, and therefore are relevant to understanding the interaction of the antibiotic with membranes.

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