Improved Antifungal Drug Reduces Kidney Toxicity by Fine-Tuning Sterol Extraction
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Improved Antifungal Drug Reduces Kidney Toxicity by Fine-Tuning Sterol Extraction
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Improved Antifungal Drug Reduces Kidney Toxicity by Fine-Tuning Sterol Extraction
Amphotericin B (AmB), a fungal-derived antifungal agent, has been a last line of defense against severe fungal infections for decades. However, its sponge-like aggregation mechanism, binding to a molecule called ergosterol (present in bacterial and fungal cells, analogous to mammalian cholesterol), leads to significant toxicity in the human body, especially in the kidneys. It was unclear whether this toxicity resulted from the same mechanism that causes fungal cell death.
On November 8, 2023, a team led by Martin Burke at the University of Illinois Urbana-Champaign published a research paper titled “Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal” in the prestigious academic journal Nature.
The study focused on structural modifications of the antifungal drug AmB, resulting in the development of a compound called AM-2-19. This new compound exhibited reduced toxicity in mouse and human kidney cells while retaining its antifungal properties. This advancement holds the potential to enhance the clinical benefits and safety of treatments targeting deadly fungal infections.
The research team created analogs of AmB, altering the parts of these molecules responsible for binding with and extracting sterols. Testing these analogs in human kidney cells revealed that kidney cell death was a result of AmB binding to and extracting cholesterol from the kidney cell membrane.
Subsequently, the team designed a variant of AmB that binds to and extracts fungal ergosterol instead of mammalian cholesterol, alleviating kidney toxicity. The resulting compound, named AM-2-19, proved harmless to human kidney cells and mice while maintaining strong antifungal efficacy. This treatment also demonstrated robust resistance against antifungal drug resistance.
First author of the paper, Arun Maji, stated that AM-2-19 stands for “Arun Maji, lab notebook 2, page 19”
The preserved mechanism in many antifungal molecules suggests that this technique could be applied to reduce toxicity in other drug treatments, thereby increasing their clinical effectiveness.
Read the full paper here: Link to the article on Nature
Improved Antifungal Drug Reduces Kidney Toxicity by Fine-Tuning Sterol Extraction
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