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Sterol Extraction via Amphotericin: precision molecular changes drive kinetics

Taras Pogorelov, University of Illinois at Urbana-Champaign

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Taras Pogorelov, Kevin Cheng, Ashley Delio

Life-threatening systemic fungal infections are on the rise and their effect is particularly severe on immunocompromised patients. The estimated total cost of treatment is a continuously growing burden on the US and the World economies. Amphotericin B (AmB) is a highly effective and resistance-evasive antifungal drug which is also toxic to humans. As a result, it is used only as the last resort treatment for systemic fungal infections.

Due to its toxicity, the associated limitations on its clinical use 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 determined. We have previously showed that AmB acts by building a large extramembraous sponge that extracts sterols from the cell wall. This is in sharp contrast to the long prevailing hypothesis that AmB kills primarily by forming small ion channels.

We performed extensive collaborative studies using NMR spectroscopy, advanced synthesis, and computational approaches to build our first model of an AmB sponge. Here we propose to characterize the structure of AmB and its newly discovered variants in the sponge and capture the mechanism of AmB action in atomistic detail to reveal the source of the range of AmB sterol selectivity through the use of enhanced sampling molecular dynamics (MD) techniques, which require the petascale power of the Blue Waters. The study offers a truly remarkable opportunity to open new directions for antifungal drug design.