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Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal
Arun Maji1,2,3,4, Corinne P Soutar2,3,5, Jiabao Zhang2,3
1Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Nature
|November 8, 2023
Summary
Developing new antifungal drugs, researchers discovered that targeting fungal ergosterol extraction, not cell membranes, leads to potent and kidney-sparing polyene antifungals like AM-2-19.
Area of Science:
- Medicinal Chemistry
- Mycology
- Pharmacology
Background:
- Traditional polyene antifungal development was based on a flawed membrane permeabilization model.
- Amphotericin B, a vital antifungal, causes kidney toxicity by extracting sterols from cell membranes.
- Fungal ergosterol extraction, not membrane disruption, is the primary mechanism of amphotericin B's antifungal action.
Purpose of the Study:
- To develop potent and renal-sparing polyene antifungal agents.
- To understand and mitigate the kidney toxicity associated with amphotericin B.
- To rationally design novel antifungals by tuning molecular interaction dynamics.
Main Methods:
- Investigated the mechanism of amphotericin B's antifungal and toxic effects.
- Utilized high-resolution structural analysis of amphotericin B-sterol complexes.
- Designed and synthesized structural derivatives of amphotericin B, including AM-2-19, and evaluated their efficacy and toxicity.
Main Results:
- Identified cholesterol extraction as the driver of amphotericin B's renal toxicity.
- Developed a renal-sparing derivative (AM-2-19) that selectively and rapidly extracts fungal ergosterol without binding cholesterol.
- AM-2-19 demonstrated potent antifungal activity, resistance evasion, and efficacy in preclinical models of invasive fungal infections.
Conclusions:
- Rational design based on molecular interaction dynamics can yield improved antifungal therapies.
- Targeting ergosterol extraction offers a promising strategy for developing potent, safe, and resistance-evasive antifungals.
- The novel polyene AM-2-19 represents a significant advancement in treating life-threatening fungal infections.
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