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Cooperative Partition Model of Nystatin Interaction with Phospholipid Vesicles

Ana Coutinho ^*  and Manuel Prieto ^*

^* Centro de Química-Física Molecular, Instituto Superior Técnico, P-1049-001 Lisbon, Portugal; and Departamento de Química e Bioquímica, F.C.U.L., P-1749-016 Lisbon, Portugal

Correspondence: Address reprint requests to Dr. Manuel Prieto, Centro de Química-Física Molecular, Instituto Superior Técnico, Av. Rovisco Pais, P-1049-001 Lisbon, Portugal. Tel.: 3-51-21-841-9219; Fax: 3-51-21-846-4455; E-mail: prieto{at}alfa.ist.utl.pt.

Nystatin is a membrane-active polyene antibiotic that is thought to kill fungal cells by forming ion-permeable channels. In this report we have investigated nystatin interaction with phosphatidylcholine liposomes of different sizes (large and small unilamellar vesicles) by time-resolved fluorescence measurements. Our data show that the fluorescence emission decay kinetics of the antibiotic interacting with gel-phase 1,2-dipalmitoyl-sn-glycero-3-phosphocholine vesicles is controlled by the mean number of membrane-bound antibiotic molecules per liposome, A. The transition from a monomeric to an oligomeric state of the antibiotic, which is associated with a sharp increase in nystatin mean fluorescence lifetime from 7–10 to 35 ns, begins to occur at a critical concentration of 10 nystatin molecules per lipid vesicle. To gain further information about the transverse location (degree of penetration) of the membrane-bound antibiotic molecules, the spin-labeled fatty acids (5- and 16-doxyl stearic acids) were used in depth-dependent fluorescence quenching experiments. The results obtained show that monomeric nystatin is anchored at the phospholipid/water interface and suggest that nystatin oligomerization is accompanied by its insertion into the membrane. Globally, the experimental data was quantitatively described by a cooperative partition model which assumes that monomeric nystatin molecules partition into the lipid bilayer surface and reversibly assemble into aggregates of 6 ± 2 antibiotic molecules.

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