SCIENCE & TECHNOLOGY
AMPHOTERICIN B MYSTERY SOLVED
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Decades-long question about
ANTIFUNGAL AGENT’S MECHANISM is answered
CHEMICAL SYNTHESIS has resolved the
© 20 11 PROC. N ATL. ACAD. SCI. USA
long-standing uncertainty about how the potent but highly toxic antifungal natural product amphotericin B works. The findings could lead to rational design of analogs with fewer side effects than the natural compound. Amphotericin B, a cyclic polyene macrolide, is used to treat progressive and life-threatening fungal infections, but it has serious side effects, including potentially fatal cardiac or cardiopulmonary arrest. Scientists have known that its activity is due to formation of ion channels, but despite decades of research, they have not been able to determine how the channels assemble. Three hypotheses to explain how amphotericin B molecules gang up to create cell-killing ion channels in fungal cell membranes differ in the molecular interactions that drive ion-channel formation. In one model, mycosamine and carboxylate groups on neighboring amphotericin B molecules
form noncovalent bonds. In the second model, mycosamine and/or carboxylate groups form polar interactions with head groups of membrane phospholipids. In the third, the mycosamine and/or carboxylate groups bind to membrane-embedded sterols such as ergosterol and cholesterol. THIS LAST MODEL is the correct one,
Martin D. Burke and coworkers at the University of Illinois, Urbana-Champaign, report in a recent paper (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.1015023108). Burke’s team came to this conclusion by synthesizing and testing derivatives of amphotericin B that lack the mycosamine group, the carboxylate group, or both. They also found that amphotericin B requires the mycosamine group—but not the carboxylate—for its molecules to interact with ergosterol or cholesterol and assemble into ion channels. Maciej Baginski, an expert on the mechanism of action of antifungal polyene macrolide antibiotics at OH Gdansk University of TechnolHO CO2– + ogy, in Poland, comments that O NH3 the finding “that amphotericin B HO O O OH molecules without the carboxyl group can still form channels HO OH and exhibit antifungal activity is a very new and rather surprising OH observation from the perspecHO tive of all 50 years of studies on H the molecular mechanism of H amphotericin B action.” OH DEATH RING The findings “will help focus OH Computer modeling efforts toward the rational opsuggests a set of timization of the therapeutic O eight amphotericin index of this clinically vital but O B molecules forms also highly toxic antimycotic,” an ion channel in a Burke and coworkers note in yeast cell membrane. their paper. “These studies vivHO A polar binding interaction idly demonstrate the power of (right) between ergosterol synthesis-enabled functional (green) and the mycosamine group (blue) of group deletions to illuminate amphotericin B enables the drug to form the highly elusive fundamental unchannels, which kill the yeast. derpinnings of small-molecule function.”—STU BORMAN WWW.CEN-ONLINE.ORG
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