Increase of reactive oxygen species contributes to growth inhibition by fluconazole in Cryptococcus neoformans

Nadir Hani Dbouk,Madison Bailey Covington,Srikripa Chandrasekaran,Kenny Nguyen

doi:10.1186/s12866-019-1606-4

Nadir Hani Dbouk, Madison Bailey Covington + Show 2 more

Open Access

https://doi.org/10.1186/s12866-019-1606-4

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Journal: BMC microbiology	Publication Date: Nov 6, 2019
Citations: 23	License type: open-access

Affiliation: Furman University

Abstract

BackgroundCryptococcus neoformans, a basidiomycetous yeast, is a fungal pathogen that can colonize the lungs of humans causing pneumonia and fungal meningitis in severely immunocompromised individuals. Recent studies have implied that the antifungal drug fluconazole (FLC) can induce oxidative stress in C. neoformans by increasing the production of reactive oxygen species (ROS), as presence of the antioxidant ascorbic acid (AA) could reverse the inhibitory effects of FLC on C. neoformans. However, in Candida albicans, AA has been shown to stimulate the expression of genes essential for ergosterol biosynthesis. Hence, the contribution of ROS in FLC-mediated growth inhibition remains unclear.ResultsIn order to determine whether counteracting ROS generated by FLC in C. neoformans can contribute to diminishing inhibitory effects of FLC, we tested three other antioxidants in addition to AA, namely, pyrrolidine dithiocarbamate (PDTC), retinoic acid (RA), and glutathione (GSH). Our data confirm that there is an increase in ROS in the presence of FLC in C. neoformans. Importantly, all four antioxidants reversed FLC-mediated growth inhibition of C. neoformans to various extents. We further verified the involvement of increased ROS in FLC-mediated growth inhibition by determining that ROS-scavenging proteins, metallothioneins (CMT1 and CMT2), contribute to growth recovery by PDTC and AA during treatment with FLC.ConclusionOur study suggests that ROS contributes to FLC-mediated growth inhibition and points to a complex nature of antioxidant-mediated growth rescue in the presence of FLC.

Highlights

Cryptococcus neoformans, a basidiomycetous yeast, is a fungal pathogen that can colonize the lungs of humans causing pneumonia and fungal meningitis in severely immunocompromised individuals
We wished to determine whether antioxidants with diverse chemical structures and modes of action could alleviate FLC-mediated growth inhibition of C. neoformans
Our study revealed that all the antioxidants tested (AA, retinoic acid (RA), pyrrolidine dithiocarbamate (PDTC), and GSH) can rescue cells from cytokinesis defects caused by FLC, but not all antioxidants could rescue growth inhibition due to FLC to the same extent

Summary

Introduction

Cryptococcus neoformans, a basidiomycetous yeast, is a fungal pathogen that can colonize the lungs of humans causing pneumonia and fungal meningitis in severely immunocompromised individuals. Cryptococcal meningitis caused by Cryptococcus neoformans is the leading cause of fungal central nervous system infection in the world, especially among persons suffering from HIV/AIDS [2, 3]. Compared to other anti-cryptococcal drugs, fluconazole (FLC) is the more affordable and less toxic alternative, which is most commonly prescribed in geographic locations where cryptococcosis is most prevalent [7, 8]. For central nervous system infections, a combination of more expensive fungicidal drugs amphotericin B and flucytosine are administered [9, 10]; the combination of these two drugs produces more toxic side effects for the host

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