Safe Antifungal

Invasive fungal infections represent a major and growing health threat, causing millions of deaths worldwide each year. This problem is being amplified by a global rise in multidrug-resistant fungal pathogens. The most powerful and resistance-evasive antifungal medicine, a naturally occurring small molecule called amphotericin B, is unfortunately highly toxic to the kidneys, which has for more than half a century severely limited its use. We thus launched a mission to eliminate this renal toxicity and (finally!) unleash the antifungal potential of this billion-year head-start from nature. Leveraging the block chemistry that is foundational for Molecule Make Lab’s discovery engine, we first discovered that amphotericin B primarily kills cells via a mechanism that is different than what appears in all the textbooks. It turns out that amphotericin B primarily forms a sponge-like aggreagate on the surface of cells that rapidly extracts sterol molecules from membranes, thus killing the cells. Block chemistry-enabled discovery of this “sterol sponge” mechanism ultimately enabled rational design of a chemically modified version of amphotericin B, dubbed AM-2-19, that extracts sterols from fungi but not human cells. This compound was licensed to a biopharmaceutical company called Sfunga Therapeutics (recently renamed Elion Therapeutics) and recently entered clinical trials with Fast Track Designation by the U.S. Food and Drug Administration.

Publication:

Nature – Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal

Highlighted:

Nature – Synthetic drug kills fungi but spares kidney cells

Science – New antifungal kills without toxic side effects

Fierce Biotech – Potent new drug has all the power of nature’s strongest antibiotic, without the toxicity

Genetic Engineering & Biotechnology News – Researchers Tweak Antifungal Drug to Turn “Ampho-terrible” into “Ampho-terrific”