Fungal infections pose a significant public health crisis that is only worsening over time. These infections have the potential to spread rapidly and cause exponential harm, similar to how COVID-19 affected the world. Currently, one of the most powerful antifungal drugs available is Amphotericin B (AmB), which is produced naturally by bacteria. AmB is known for its exceptional ability to kill fungi, but unfortunately, it is also highly toxic to the human body, particularly the kidneys. This toxicity has limited its usage to a last-resort treatment option.
Researchers at the University of Illinois Urbana-Champaign, in collaboration with the University of Wisconsin-Madison, have dedicated years of study to understand AmB’s mechanism and to develop a derivative that retains its antifungal potency without harming humans. Through their investigations, they discovered that AmB kills fungi by acting as a sponge to extract ergosterol, a crucial component of fungal cells. However, they also found that AmB extracts cholesterol, the most common sterol in human cells, leading to its toxicity in humans.
Armed with this knowledge, the research team focused on modifying AmB to reduce its interaction with cholesterol and thereby decrease its toxicity. They utilized atomic-resolution models to identify subtle differences in the binding interactions between AmB and each sterol. This structural information, combined with functional and computational studies, provided valuable insights for modifying AmB.
Building upon their findings, the researchers began synthesizing and testing derivatives of AmB with slight changes in the region that binds to ergosterol and cholesterol. Their goal was to maintain the efficacy of ergosterol removal while reducing toxicity. They collaborated with experts and utilized state-of-the-art facilities to test the most promising derivatives in vitro assays, cell cultures, and eventually in live mice.
Out of all the derivatives, one molecule, named AM-2-19, exhibited exceptional properties. This molecule demonstrated kidney-sparing capabilities, resistance evasion, and broad-spectrum efficacy against over 500 clinically relevant fungal species. In fact, it either mimicked or surpassed the efficacy of currently available antifungal drugs in various locations. The researchers conducted extensive tests, including screening for toxicity in human blood and kidney cells, as well as evaluating its effectiveness in mouse models of common fungal infections.
AmB has long been known to medical professionals as “ampho-terrible” due to its harsh effects on patients. However, the researchers are excited about the potential of AM-2-19, as it decouples efficacy from toxicity, turning “ampho-terrible” into “ampho-terrific.” Despite these significant findings, further clinical studies are necessary to determine if AM-2-19 can translate its potential benefits to human patients. As a first step towards clinical application, AM-2-19 has been licensed to Sfunga Therapeutics and is currently undergoing Phase 1 clinical trials.
The development of AM-2-19, a modified derivative of Amphotericin B, brings new hope in the battle against fungal infections. By reducing its toxicity while retaining its potent antifungal properties, AM-2-19 shows promise in becoming a powerful ally in the fight against fungal infections. The researchers’ deep understanding of AmB’s mechanism, combined with their extensive molecular studies, has paved the way for this breakthrough. While further research is needed, AM-2-19 represents a significant step forward in addressing the urgent and growing threat of fungal infections.