Quinone derivatives isolated from the endolichenic fungus Phialocephala fortinii are Mdr1 modulators that combat azole resistance in Candida albicans.

Fei Xie,Hongxiang Lou,Ying Li,Sha Zheng,Hongzhuo Shi,Wenqiang Chang,Wei Li,Ming Zhang

doi:10.1038/srep33687

Fei Xie, Hongxiang Lou + Show 6 more

Open Access

https://doi.org/10.1038/srep33687

Copy DOI

Journal: Scientific reports	Publication Date: Sep 1, 2016
Citations: 33	License type: CC BY 4.0

Affiliation: Shandong University

Abstract

One of the main azole-resistance mechanisms in Candida pathogens is the upregulation of drug efflux pumps, which compromises the efficacy of azoles and results in treatment failure. The combination of azole-antifungal agents with efflux pump inhibitors represents a promising strategy to combat fungal infection. High-throughput screening of 150 extracts obtained from endolichenic fungal cultures led to the discovery that the extract of Phialocephala fortinii exhibits potent activity for the reversal of azole resistance. From P. fortinii cultures, a total of 15 quinone derivatives, comprising 11 new derivatives and 4 known compounds, were obtained. Among these compounds, palmarumycin P3 (3) and phialocephalarin B (8) specifically modulate the expression of MDR1 to inhibit the activity of drug efflux pumps and therefore reverse azole resistance. The present study revealed Mdr1 targeting as an alternative mechanism for the discovery of new agents to fight antifungal drug resistance.

Highlights

Candida albicans is the most frequent human commensal opportunistic fungal pathogen, resulting in high morbidity and mortality, in immunosuppressed patients[1,2,3]
We examined the reversal of azole resistance in 150 extracts from endolichenic fungi cultures, leading to the discovery that the extract of Phialocephala fortinii displayed potent activity to reverse azole resistance
Palmarumycin P3 (3) and phialocephalarin B (8), which two representatives of the compounds obtained, could modulate the expression of MDR1 to inhibit the activity of drug efflux pumps and reverse azole resistance

Summary

Introduction

Candida albicans is the most frequent human commensal opportunistic fungal pathogen, resulting in high morbidity and mortality, in immunosuppressed patients[1,2,3]. The mechanisms leading to azole resistance include alterations in the sterol biosynthetic pathway, increased expression of the ERG11 gene encoding the target enzyme of fluconazole (FLC), sterol 14α-demethylase (Erg11), mutations in the ERG11 gene resulting in the reduced affinity of Erg[11] to FLC, and the overexpression of genes encoding membrane transport proteins, which pump FLC out of the cell[7,8,9] Among these pumps, the overexpression of drug transporters is a principal mechanism utilized by Candida species to alleviate antibiotic stress through a reduction in the intracellular accumulation. Palmarumycin P3 (3) and phialocephalarin B (8), which two representatives of the compounds obtained, could modulate the expression of MDR1 to inhibit the activity of drug efflux pumps and reverse azole resistance

Methods

Results

Conclusion