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Decoding host cell interaction- and fluconazole-induced metabolic alterations and drug resistance in Candida auris
Samah H H Ismail1,2, Rania Hamdy1,3, Alaa M Altaie1
1Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates.
Abstract:
Candida auris is an emerging drug-resistant pathogen associated with high mortality rates. This study aimed to explore the metabolic alterations and associated pathogenesis and drug resistance in fluconazole-treated Candida auris-host cell interaction. Compared with controls, secreted metabolites from fluconazole-treated C. auris and fluconazole-treated C. auris-host cell co-culture demonstrated notable anti-Candida activity. Fluconazole caused significant reductions in C. auris cell numbers and aggregated phenotype. Metabolites produced by C. auris with potential fungal colonization, invasion, and host immune evasion effects were identified. Metabolites known to enhance biofilm formation produced during C. auris-host cell interaction were inhibited by fluconazole. Fluconazole enhanced the production of metabolites with biofilm inhibition activity, including behenyl alcohol and decanoic acid. Metabolites with potential Candida growth inhibition activity such as 2-palmitoyl glycerol, 1-tetradecanol, and 1-nonadecene were activated by fluconazole. Different patterns of proinflammatory cytokine expression presented due to fluconazole concentration and host cell type (fibroblasts versus macrophages). This highlights the immune response's complexity, emphasizing the necessity for additional research to comprehend cell-type-specific responses to antifungal therapies. Both host cell interaction and fluconazole treatment increased the expression of CDR1 and ERG11 genes, both associated with drug resistance. This study provides insights into pathogenesis in C. auris due to host cell interaction and fluconazole treatment. Understanding these interactions is crucial for enhancing fluconazole sensitivity and effectively combating C. auris.
Insights
Fluconazole treatment alters Candida auris metabolism, reducing fungal load and biofilm formation. This study reveals key metabolic shifts impacting pathogenesis and drug resistance, crucial for developing new antifungal strategies against this emerging pathogen.
Area of Science:
- Medical Mycology
- Antimicrobial Resistance
- Drug Discovery
Background:
- Candida auris is a multidrug-resistant fungal pathogen causing severe infections with high mortality.
- Understanding host-pathogen interactions and metabolic adaptations is crucial for effective antifungal treatment.
- Fluconazole is a common antifungal, but resistance is a growing concern.
Purpose of the Study:
- To investigate metabolic alterations in Candida auris during host cell interaction under fluconazole treatment.
- To explore the impact of these metabolic changes on pathogenesis and drug resistance.
- To identify specific metabolites involved in anti-Candida activity and immune response modulation.
Main Methods:
- Co-culture of fluconazole-treated Candida auris with host cells (fibroblasts and macrophages).
- Metabolomic analysis of secreted metabolites.
- Assessment of fungal cell number, phenotype, biofilm formation, and gene expression (CDR1, ERG11).
- Analysis of proinflammatory cytokine expression.
Main Results:
- Fluconazole treatment reduced Candida auris cell numbers and aggregation.
- Secreted metabolites showed anti-Candida activity, with fluconazole inhibiting biofilm-enhancing metabolites and activating biofilm-inhibiting ones (e.g., behenyl alcohol, decanoic acid).
- Metabolites with potential growth inhibition (e.g., 2-palmitoyl glycerol) were activated.
- Proinflammatory cytokine expression varied based on fluconazole concentration and host cell type.
- Host cell interaction and fluconazole increased expression of drug resistance genes (CDR1, ERG11).
Conclusions:
- Fluconazole induces significant metabolic changes in Candida auris, affecting its virulence and drug resistance.
- Specific metabolites identified possess anti-Candida and biofilm-inhibiting properties.
- Host cell type influences immune response complexity, necessitating further research for targeted antifungal therapies.
- Understanding these interactions is vital for improving fluconazole efficacy against Candida auris.
