Research conducted by American scientists indicates that a structurally modified antifungal drug exhibits reduced toxicity in both mouse and human kidney cells while retaining its antifungal properties. This advancement may enhance the clinical benefits and safety of such treatments against life-threatening fungal infections. The relevant study was published on November 9th in Nature.
Amphotericin B (AmB) is a naturally occurring antifungal agent produced by bacteria and has been used as a last resort against severe fungal infections for decades. It forms a sponge-like aggregate that binds to molecules called ergosterols (present in bacterial and fungal cells, akin to mammalian cholesterol). This binding leads to the extraction of ergosterols from the cell membrane, resulting in fungal cell death.
Despite its efficacy in treatment, AmB poses significant toxicity to the human body, particularly to kidney cells. However, it has remained unclear whether this toxicity stems from the same mechanism that leads to fungal cell death.
Martin Burke and colleagues from the University of Illinois at Urbana-Champaign created analogs of AmB, altering the portions of these molecules responsible for binding to sterols, with the aim of observing how these changes affect biological activity. Testing these analogs on human kidney cells revealed that kidney cell death resulted from AmB's binding to and extraction of cholesterol from the kidney cell membrane.
The researchers then designed a variant of AmB that binds to and extracts ergosterol from fungal cells rather than mammalian cholesterol, thus mitigating renal toxicity. The resulting compound (referred to as AM-2-19 by the authors) was found to be non-toxic to human kidney cells and mice kidneys while still demonstrating effective antifungal therapy. This treatment also exhibits relatively strong resistance against antimicrobial drug resistance.
"'AM-2-19' stands for 'Arun Maji, lab notebook 2, page 19'," said Arun Maji, the first author of the paper from the University of Illinois at Urbana-Champaign. "In hindsight, we should have given it a different name."
This mechanism of action has been preserved in many antifungal molecules, leading researchers to believe that this technique could be employed to reduce toxicity in more drug therapies, thereby enhancing their clinical effectiveness.
The mechanism of action of an important yet highly toxic antifungal agent has been revealed at high resolution. The self-assembled amphiphilic amphotericin B sponge can rapidly extract sterols from cells, bringing about a groundbreaking renal protective antifungal. Image credit: Jose Vazquez
Researchers extensively evaluated the efficacy and toxicity of promising candidate compounds, both in vitro and in vivo. From left to right in the image are: Arun Maji, Agnieszka Lewandowska, and Corinne Soutar. Image credit: Michelle Hassel.
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