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Broth Microdilution In Vitro Screening: An Easy and Fast Method to Detect New Antifungal Compounds
Published on: February 14, 2018
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Targeting the polyene chain represents an adjuvant strategy for optimizing polyene antifungals.
Yishan Zhang1,2,3, Xiaocong Liu1,3, Luobei Weng1,3
1State Key Laboratory of Bioactive Molecules and Druggability Assessment, The First Affiliated Hospital of Jinan University Guangzhou Guangdong 510630, China.
Summary
Researchers discovered that the polyene chain of polyene antifungals (PAs) acts as a molecular switch. Coupling PAs with adjuvants like vitamin D3 reduces kidney toxicity and enhances antifungal effectiveness.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Mycology
Background:
- Polyene antifungals (PAs) are crucial for treating severe fungal infections.
- PAs cause dose-dependent nephrotoxicity due to binding to cholesterol in kidney cells, similar to their target ergosterol in fungi.
Purpose of the Study:
- To explore the potential of the polyene chain in PAs for optimization.
- To develop a strategy for attenuating PA-induced nephrotoxicity while enhancing antifungal efficacy.
Main Methods:
- Investigated the polyene chain's role as a molecular switch.
- Utilized hydrophobic coupling with clinically approved drug adjuvants.
- Analyzed conformational rearrangements and modulated binding to membrane lipids.
Main Results:
- The polyene chain, when coupled with adjuvants, triggers conformational changes in PAs.
- This modulation asymmetrically affects binding to cholesterol and ergosterol, reducing kidney toxicity.
- Vitamin D3 showed significant adjuvant activity in preclinical models and retrospective clinical data.
Conclusions:
- Exploiting the polyene chain as a molecular switch offers a novel strategy for PA optimization.
- Adjuvant coupling can concurrently reduce nephrotoxicity and potentiate antifungal effectiveness.
- Vitamin D3 presents a promising adjuvant for clinical application with PAs.
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