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Increase of reactive oxygen species contributes to growth inhibition by fluconazole in Cryptococcus neoformans
Nadir Hani Dbouk1, Madison Bailey Covington1, Kenny Nguyen1
1Department of Biology, Furman University, Greenville, SC, USA.
Background:
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. 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.
Results:
In 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.
Conclusion:
Our 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.
Insights
Antioxidants like ascorbic acid can reverse fluconazole
Area of Science:
- Mycology
- Antifungal Drug Research
- Oxidative Stress Biology
Background:
- Cryptococcus neoformans is a fungal pathogen causing pneumonia and meningitis in immunocompromised individuals.
- The antifungal drug fluconazole (FLC) may induce oxidative stress in C. neoformans by increasing reactive oxygen species (ROS).
- Ascorbic acid (AA) reversed FLC's inhibitory effects, but its role in ergosterol biosynthesis in other fungi complicates understanding ROS contribution.
Purpose of the Study:
- To investigate if counteracting FLC-induced ROS in C. neoformans diminishes FLC's inhibitory effects.
- To explore the role of ROS in FLC-mediated growth inhibition and antioxidant-mediated rescue.
Main Methods:
- Tested four antioxidants (ascorbic acid, pyrrolidine dithiocarbamate, retinoic acid, glutathione) for their ability to reverse FLC's inhibitory effects on C. neoformans.
- Confirmed increased ROS production in C. neoformans treated with FLC.
- Assessed the role of ROS-scavenging metallothioneins (CMT1 and CMT2) in fungal growth recovery.
Main Results:
- FLC treatment significantly increased ROS levels in C. neoformans.
- All four tested antioxidants reversed FLC-mediated growth inhibition to varying degrees.
- Metallothioneins (CMT1 and CMT2) were found to contribute to fungal growth recovery when treated with FLC and antioxidants.
Conclusions:
- Reactive oxygen species (ROS) play a significant role in fluconazole-mediated growth inhibition of Cryptococcus neoformans.
- Antioxidant-mediated growth rescue in the presence of FLC is complex and involves ROS-scavenging mechanisms.
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