Arun Maji Credit: Michelle Hassel, University of Illinois
A collaboration between researchers at the University of Illinois Urbana-Champaign and the University of Wisconsin-Madison has discovered a novel antifungal treatment void of human toxicity. The treatment is a safer modified form of an existing antifungal treatment that damages the patient's kidneys.
Despite being a powerful antifungal treatment, Amphotericin B has been historically used as a last line of defense to treat fungal infections due to its toxicity to humans. In the study, published in Nature, researchers discovered that by tweaking the structure of Amphotericin B its antifungal properties can be preserved while eliminating its toxicity to humans.
"Fungal infections are a public health crisis that is only getting worse. And they have the potential, unfortunately, of breaking out and having an exponential impact, kind of like COVID-19 did. So let's take one of the powerful tools that nature developed to combat fungi and turn it into a powerful ally," said Dr. Martin D. Burke, Illinois professor of chemistry.
Burke and his colleagues have spent years studying AmB to create a treatment that can be used as an antifungal without toxicity to humans. By teaming up with researchers at the University of Wisconsin-Madison and utilizing solid-state nuclear magnetic resonance the team uncovered that AmB works by acting similar to a sponge, extracting ergosterol from the fungal cells. Similarly, AmB harms humans by extracting cholesterol from kidney cells. The team also resolved the atomic structure of AmB when bound to both cholesterol and ergosterol.
"Using this structural information along with functional and computational studies, we achieved a significant breakthrough in understanding how AmB functions as a potent fungicidal drug," said Professor Chad Rienstra. "This provided the insights to modify AmB and tune its binding properties, reducing its interaction with cholesterol and thereby reducing the toxicity."
With this information, the team began synthesizing derivatives with changes to the region that binds to cholesterol and ergosterol. After in vitro assay testing, cell culture, and eventually live mice testing, one molecule called AM-2-19 stood out.
"This molecule is kidney-sparing, it is resistance evasive and it has broad spectrum efficacy," said Arun Maji, a co-first author of the paper. "We tested this molecule against over 500 different clinically relevant pathogen species in four different locations. And this molecule completely surprised us by either mimicking or surpassing the efficacy of current clinically available antifungal drugs."
AM-2-19 has recently entered phase 1 trials after being licensed to Sfunga Therapeutics, bringing it one step closer to clinical applications.