Fructose Induces Fluconazole Resistance in Candida albicans through Activation of Mdr1 and Cdr1 Transporters.

Jakub Suchodolski,Anna Krasowska

doi:10.3390/ijms22042127

Abstract

Candida albicans is a pathogenic fungus that is increasingly developing multidrug resistance (MDR), including resistance to azole drugs such as fluconazole (FLC). This is partially a result of the increased synthesis of membrane efflux transporters Cdr1p, Cdr2p, and Mdr1p. Although all these proteins can export FLC, only Cdr1p is expressed constitutively. In this study, the effect of elevated fructose, as a carbon source, on the MDR was evaluated. It was shown that fructose, elevated in the serum of diabetics, promotes FLC resistance. Using C. albicans strains with green fluorescent protein (GFP) tagged MDR transporters, it was determined that the FLC-resistance phenotype occurs as a result of Mdr1p activation and via the increased induction of higher Cdr1p levels. It was observed that fructose-grown C. albicans cells displayed a high efflux activity of both transporters as opposed to glucose-grown cells, which synthesize Cdr1p but not Mdr1p. Additionally, it was concluded that elevated fructose serum levels induce the de novo production of Mdr1p after 60 min. In combination with glucose, however, fructose induces Mdr1p production as soon as after 30 min. It is proposed that fructose may be one of the biochemical factors responsible for Mdr1p production in C. albicans cells.

Highlights

Candida albicans is an opportunistic fungal pathogen responsible for high morbidity and mortality in immunocompromised patients [1]
One of the underlying processes responsible for MDR in C. albicans is the increased synthesis of membrane efflux transporters such as Cdr1p and Cdr2p, which belong to the ATP-Binding Cassette (ABC) family, and Mdr1p, which belongs to the Major Facilitator
Fluctuations in the availability of various carbon sources have a profound effect on the physiology of C. albicans, including changes in the gene expression, which may result in drug resistance [22]

Summary

Introduction

Candida albicans is an opportunistic fungal pathogen responsible for high morbidity and mortality in immunocompromised patients [1]. Infections caused by C. albicans are recurrent and difficult to treat due to the ability of fungal cells to acquire a multidrug-resistant (MDR) phenotype [3]. In 2019, it was estimated that up to 20% of clinical Candida spp. isolates exhibit azole resistance [4]. One of the underlying processes responsible for MDR in C. albicans is the increased synthesis of membrane efflux transporters such as Cdr1p and Cdr2p, which belong to the ATP-Binding Cassette (ABC) family, and Mdr1p, which belongs to the Major Facilitator. Each transporter possesses different substrate specificities, all three can export fluconazole (FLC), the most common therapeutic anticandidal azole [5]

Objectives

Methods

Results