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| 2023-11-15 13:10:24 | onclick： | Improved antifungal agent renal toxicity reduction |
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A structurally modified antifungal drug reduces its toxicity in mouse and human kidney cells while maintaining its antibacterial properties, US scientists have shown.This development may increase the clinical efficacy and safety of such treatments against deadly fungal infections.The study was published in Nature on November 9.
Amphotericin (AmB) is a bacterial antifungal agent that has been used for decades as the last line of defense against severe fungal infections.It forms a sponge-like coagulation that binds to molecules called ergotosteroids, which are found in bacteria and fungal cells and act like mammalian cholesterol.This binding causes ergotosteroids to pull out of the cell membrane, causing fungal cell death.
Despite its therapeutic effectiveness, AmB is highly toxic to humans, especially kidney cells.However, it is unclear whether this toxicity is due to the same mechanism that causes fungal cell death.
Martin Burke and colleagues at the University of Illinois-Champaign created analogues of AmB that altered the steroid-binding parts of these molecules to see how these changes affect biological activity.These analogues were tested in human kidney cells and found that renal cell death was due to the binding and extraction of cholesterol from AmB and renal cell membranes.
The researchers then devised a variant of AmB that binds and extracts the fungal ergotic steroid instead of mammalian cholesterol, which relieves kidney toxicity.The resulting compounds (named AM-2-19 by the authors) are harmless to the kidneys in human kidney cells and mice, and are still effective as antifungal treatments.This treatment is also relatively resistant to antimicrobial resistance.
AM-2-19 means 'Arun Maji, transcript 2, p. 19'.Arun Maji, lead author of the paper and University of Illinois-Champaign, said, "I should have given it a different name."
This mechanism has been retained in many antifungal molecules, and researchers believe the technique could be used to reduce toxicity and increase clinical effectiveness in more medications.
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