While amphotericin's efficacy is clear, the reasons for its remarkable infection-fighting ability remained uncertain. Doctors and researchers do know that amphotericin creates ion channels that permeate the cell membrane. Physicians have long assumed that this was the mechanism that killed the infection, and possibly the patient's cells as well. This widely accepted dogma appears in many scientific publications and textbooks.
However, several studies have shown that channel formation alone may not be the killing stroke. In fact, as Burke's group discovered, the mechanism is much simpler.
Amphotericin binds to a lipid molecule called ergosterol, prevalent in fungus and yeast cells, as the first step in forming the complexes that make ion channels. But Burke's group found that, to kill a cell, the drug doesn't need to create ion channels at all it simply needs to bind up the cell's ergosterol.
Burke's group produced a derivative of amphotericin using a molecule synthesis method Burke pioneered called iterative cross-coupling (ICC), a way of building designer molecules using simple chemical "building blocks" called MIDA boronates joined together by one simple reaction. They created a derivative that could bind ergosterol but could not form ion channels, and tested it against the original amphotericin.
If the widely accepted model was true, and ion channel formation was the drug's primary antifungal action, then the derivative would not be able to wipe out a yeast colony. But the ergosterol-binding, non-channel-forming derivative was almost equally potent to nat
|Contact: Liz Ahlberg|
University of Illinois at Urbana-Champaign