Echinocandins Localized to the Target-Harboring Cell Surface Are Not Degraded but Those Entering the Vacuole Are

Qais Z. Jaber, Dana Logviniuk, Adi Yona, Micha Fridman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Echinocandin antifungal drugs have a broad spectrum of activities and excellent safety profiles. These agents noncompetitively inhibit the formation of the major polysaccharide component of the fungal cell wall, a reaction catalyzed by the membrane-bound β-glucan synthase (GS) protein complex. We have developed fluorescent probes of three echinocandin drugs: caspofungin (CSF), anidulafungin (ANF), and rezafungin (RZF). Fluorescent echinocandins had the same spectrum of activities as the parent echinocandins, supporting the fact that conjugation of the dye did not alter their mode of action. Of the three echinocandins, ANF has the most potent in vitro activity. Investigation of the subcellular distribution of the fluorescent echinocandins in live Candida yeast cells revealed that despite their high structural similarity, each of the drug probes had a unique subcellular distribution pattern. Fluorescent CSF, which is the least potent of the three echinocandins, accumulated in Candida vacuoles; fluorescent ANF localized in the extracellular environment and on the yeast cell surface where the target GS resides; and fluorescent RZF was partitioned between the surface and the vacuole over time. Recovery of fluorescent CSF from Candida cells revealed substantial degradation over time; functional vacuoles were necessary for this degradation. Under the same conditions, fluorescent ANF was not degraded. This study supports the “target-oriented drug subcellular localization” principle. In the case of echinocandins, localization to the cell surface can contribute to improved potency and accumulation in vacuoles induces degradation leading to drug deactivation.

Original languageEnglish
Pages (from-to)1153-1163
Number of pages11
JournalACS Chemical Biology
Issue number5
StatePublished - 20 May 2022


FundersFunder number
Teva Pharmaceutical Industries
American Neuromuscular Foundation
Israel Science Foundation179/19
Council for Higher Education


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