Abstract
Amphotericin B (AmB, 1) is a polyene antibiotic that has been used for treatment of systemic fungal infections for over 50 years. It is generally accepted that an ion-permeable channel formed across cell membrane is responsible for the pharmacological activity of AmB, and the higher affinity of AmB to ergosterol over cholesterol accounts for selective toxicity to fungi. In spite of such pharmacological significance, sterol recognition mechanism of AmB molecule remains elusive. To elucidate the molecular interaction mechanism between AmB and sterols, we chemically prepared several ergosterol analogues, which had the different number of alicyclic double-bonds or side chain structures. Then the analogues were subjected to membrane-permeabilizing activity assays with use of phosphatidylcholine liposomes to evaluate the potentiation effect of AmB's activity. The results indicate that the position of double-bonds and side chain structures of sterols are critical for the membrane activity of AmB. To further investigate the structural requirements for their bimolecular interactions, we examined conformations of AmB and sterols and deduced that close proximity between a sterol molecule and the heptaene group of AmB probably is essential for high affinity.
