Mechanism of action of amphotericin

Researchers now understand the mechanism of action of amphotericin, an antifungal drug that has been in use for more than 50 years -- even though it is nearly as toxic to human cells as it is to the microbes it attacks.

Studies have found evidence that amphotericin opens up ion channels in membranes, perhaps making them leakier to charged atoms that could disrupt a cell. Most scientists assumed that this was the drug's main mode of action. But the evidence also suggested that amphotericin interacted with sterols, such as cholesterol in animal cells and ergosterol in yeast. Rienstra and Burke focused on amphotericin's influence on sterols, hypothesizing that this might be a key to its toxicity.

The initial data supported this idea, indicating that very little of the drug -- less than 5 percent -- actually formed channels in membranes. Using nuclear magnetic resonance and other experimental tools, a research team have found that most of the amphotericin aggregates on the exterior of membranes, extracting sterols out of membranes like a sponge. Cell death follows soon after.

The research was carried out at Chad Rienstra. A report of the new findings has been published in Nature Chemical Biology:

Thomas M Anderson, Mary C Clay, Alexander G Cioffi, Katrina A Diaz, Grant S Hisao, Marcus D Tuttle, Andrew J Nieuwkoop, Gemma Comellas, Nashrah Maryum, Shu Wang, Brice E Uno, Erin L Wildeman, Tamir Gonen, Chad M Rienstra, Martin D Burke. Amphotericin forms an extramembranous and fungicidal sterol sponge. Nature Chemical Biology, 2014; DOI: 10.1038/nchembio.1496

Posted by Tim Sandle