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| 2024-03-01 11:11:49 | onclick： | Modified antifungal agents reduce renal toxicity |
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A structurally modified antifungal drug has been shown to be less toxic in mouse and human kidney cells while maintaining its antibacterial properties.This advancement may increase the clinical efficacy and safety of such treatments against deadly fungal infections.The study was published in Nature on November 9.
Amphotomycin (AmB) is a bacterial-produced antifungal agent that has been used for decades as the last line of defense against serious fungal infections.It forms a sponge-like condensation that binds to molecules called ergosterols (found in bacterial and fungal cells that act like mammalian cholesterol).This binding causes ergosteroid to be withdrawn from the cell membrane, leading to fungal cell death.
Despite its therapeutic effectiveness, AmB is highly toxic to humans, especially kidney cells.But whether this toxicity is due to the same mechanism that causes fungal cell death is unclear.
Martin Burke and colleagues at the University of Illinois at Urbana-Champaign created some AmB analogs that altered the portion of these molecules that bind to steroids, aiming to see how these changes affect biological activity.Tests with these analogues in human kidney cells found that kidney cell death was due to the binding and extraction of AmB to the cholesterol in the kidney cell membrane.
The researchers then designed a variant of AmB that binds and extracts fungal ergosterols, not mammalian cholesterol, to ease kidney toxicity.The resulting compound (which the authors named AM-2-19) is harmless to the kidneys in human kidney cells and mice, while still working well as an antifungal therapy.This treatment is also relatively resistant to antimicrobial resistance.
AM-2-19 means 'Arun Maji, Record of Experiments 2, p. 19'.Arun Maji of the University of Illinois at Urbana-Champaign, the paper's first author, said, "I knew I'd give it a different name."
This mechanism of action is preserved in many antifungal molecules, and the researchers believe that this technique can be used to reduce toxicity in more drug treatments and increase their clinical effectiveness.
The mechanism of action of an important but highly toxic antifungal agent was revealed at high resolution1.Self-assembled amphotericin B sponges can quickly extract steroids from cells, a level derived from understanding that has led to a breakthrough in kidney protection as an antifungal agent.
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