How Amphotericin, the antifungal drug of last resort, captures sterols: the good and the bad?

Taras Pogorelov, University of Illinois at Urbana-Champaign

Usage Details

Life-threatening systemic fungal infections are on the rise and their effect is particular severe on immunocompromised patients. The estimated total cost of treatment is a continuously growing burden on the U.S. and the World economies. Amphotericin B (AmB) is a highly effective and resistance-evasive antifungal drug, but is unfortunately also toxic to humans. As a result, it is used only as the last resort and at systemic fungal infections, and the associated limitations on its dosing have caused the mortality rate for these infections to remain near 50%.

The mechanism of AmB action is implicated in its unique capacity to evade resistance, and this mechanism remains incompletely understood. We recently showed that AmB acts by building a large extramembraous sponge that extracts sterols from the cell wall. This is in a sharp contrast to the hypothesis, prevailing for more than 50 years, that AmB kills primarily by forming small ion channels. We performed extensive collaborative studies using NMR spectroscopy, advanced synthesis, and computational approaches to build to our knowledge the first model of AmB sponge.

Here we propose to capture the mechanism of AmB action in atomistic detail and reveal the source of AmB sterol selectivity by using enhanced sampling molecular dynamics (MD) techniques, which require the petascale power of the Blue Waters. The proposed study, if successful, offers truly remarkable opportunity to open new directions for antifungal drug design.