Event
【GIR Open Seminar】 Dr. Micha Fridman / Tel Aviv University (Israel)
| Date | 2026.5.1 (15：30 - 17：00) |
|---|---|
| Venue |
Lecture Room L0831, 3rd Fl., Building 8, Koganei Campus, TUAT |
| Speaker | Dr. Micha Fridman |
| Affiliation | Tel Aviv University (Israel) |
| Title | "Chemical Probes in Antifungal Research: Decoding Mechanisms, Resistance, and Drug Discovery Concepts" ＜要旨＞ The growing prevalence of fungal infections and the rapid emergence of antifungal resistance highlight the need for deeper insight into how antifungal agents operate in living cells. To address this challenge, we have developed a comprehensive set of fluorescent chemical probes modeled on the three major classes of clinically used antifungal drugs: azoles, echinocandins, and polyenes. These probes enable direct visualization of drug localization and behavior in live fungal cells and provide a platform for dissecting mechanisms of action and resistance. Using azole-derived probes, we demonstrate that intracellular localization is a key determinant of antifungal potency, with enhanced activity observed upon accumulation in the endoplasmic reticulum, the site of the target enzyme. These probes also allow rapid detection of resistance traits, including elevated drug efflux. Fluorescent echinocandin analogues reveal that accumulation at the fungal cell surface strongly correlates with antifungal efficacy. An imaging-based uptake assay enables prediction of resistance, and structural tuning of the echinocandin scaffold restores activity against resistant strains, providing insight into structure-activity relationships and target engagement. Extending this approach, we developed a unified collection of fluorescent polyene probes derived from amphotericin B, nystatin, and natamycin. While maintaining a shared mode of action, these probes exhibit species-dependent differences in subcellular localization. Notably, resistant strains show pronounced vacuolar accumulation, suggesting drug sequestration as a resistance mechanism and providing a microscopy-based resistance marker. In a recent effort to apply a novel concept for overcoming echinocandin resistance, we identified a minimal chemical modification strategy. Selective removal of the benzylic alcohol of the nonproteinogenic amino acid L-homotyrosine in clinically used echinocandins restores potency against a broad panel of resistant Candida strains, while maintaining low toxicity toward human cells. This single-site modification provides new insight into drug–target interactions and offers a simple and effective approach to re-sensitize resistant fungal pathogens. Together, our studies establish a chemical biology framework that integrates fluorescent probe design with live-cell imaging to provide direct visual evidence of antifungal drug action and resistance, enabling new concepts for the development of more effective antifungal therapies. |
| Language | English |
| Intended for | Everyone is welcome to join |
| Organized by | Institute of Global Innovation Research, “LIFE SCIENCE” Sakurai Team |
| Contact | Institute of Global Innovation Research, Institute of Engineering Prof. Kaori Sakurai e-mail: sakuraik (at) cc.tuat.ac.jp |
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