Myriocin Enhances the Antifungal Activity of Fluconazole by Blocking the Membrane Localization of the Efflux Pump Cdr1

Overview

Journal Front Pharmacol

Date 2023 Jan 9

PMID 36618949

Authors

Hongkang Wang

Zhe Ji

Yanru Feng

Tianhua Yan

Yongbing Cao

Hui Lu

Yuanying Jiang

Affiliations

Soon will be listed here.

Abstract

Extrusion of azoles from the cell, mediated by an efflux pump Cdr1, is one of the most frequently used strategies for developing azole resistance in pathogenic fungi. The efflux pump Cdr1 is predominantly localized in lipid rafts within the plasma membrane, and its localization is sensitive to changes in the composition of lipid rafts. Our previous study found that the calcineurin signal pathway is important in transferring sphingolipids from the inner to the outer membrane. We investigated multiple factors that enhance the antifungal activity of fluconazole (FLC) using minimum inhibitory concentration (MIC) assays and disk diffusion assays. We studied the mechanism of action of myriocin through qRT-PCR analysis and confocal microscopy analysis. We tested whether myriocin enhanced the antifungal activity of FLC and held therapeutic potential using a mouse infection model. We found that this signal pathway has no function in the activity of Cdr1. We found that inhibiting sphingolipid biosynthesis by myriocin remarkably increased the antifungal activity of FLC with a broad antifungal spectrum and held therapeutic potential. We further found that myriocin potently enhances the antifungal activity of FLC against by blocking membrane localization of the Cdr1 rather than repressing the expression of Cdr1. In addition, we found that myriocin enhanced the antifungal activity of FLC and held therapeutic potential. Our study demonstrated that blocking the membrane location and inactivating Cdr1 by inhibiting sphingolipids biogenesis is beneficial for enhancing the antifungal activity of azoles against azole-resistant due to Cdr1 activation.

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