cDNA microarray analysis of differential gene expression and regulation in clinically drug-resistant isolates of Candida albicans from bone marrow transplanted patients
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Published on: January 13, 2016
Zheng Xu1, Li-Xin Zhang, Jun-Dong Zhang
1Department of Pharmacology, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, PR China.
Abstract:
Fungi have emerged as the fourth most common pathogens isolated in nosocomial bloodstream infections, and Candida albicans is the most common human fungal pathogen. Only a few antibiotics are effective in the treatment of fungal infections. In addition, the repetition and lengthy duration of fluconazole therapy has led to an increased incidence of azole resistance and treatment failure associated with C. albicans. To investigate the mechanism of drug resistance and explore new targets to treat clinically resistant fungal pathogens, we examined the large-scale gene expression profile of two sets of matched fluconazole-susceptible and -resistant bloodstream C. albicans isolates from bone marrow transplanted (BMT) patients for the first time by microarray analysis. More than 198 differentially expressed genes were identified and they were confirmed and validated by RT-PCR independently. Not surprisingly, the resistant phenotype is associated with increased expression of CDR mRNA, as well as some common genes involved in drug resistance such as CaIFU5, CaRTA2 and CaIFD6. Meanwhile, some special functional groups of genes, including ATP binding cassette (ABC) transporter genes (IPF7530, CaYOR1, CaPXA1), oxidative stress response genes (CaALD5, CaGRP1, CaSOD2, IPF10565), copper transport and iron mobilization-related genes (CaCRD1/2, CaCTR1/2, CaCCC2, CaFET3) were found to be differentially expressed in the resistant isolates. Furthermore, among these differentially expressed genes, some co-regulated with CaCDR1, CaCDR2 and CaIFU5, such as CaPDR16 and CaIFD6, have a DRE-like element and may interact with TAC1 in the promoter region. These findings may shed light on mechanisms of azole resistance in C. albicans and clinical antifungal therapy.
Insights
Candida albicans, a common cause of bloodstream infections, is developing resistance to fluconazole. This study identified 198 differentially expressed genes in resistant strains, revealing potential new targets for antifungal drug development.
Area of Science:
- Mycology
- Medical Microbiology
- Molecular Biology
Background:
- Fungal infections, particularly bloodstream infections caused by Candida albicans, are a significant healthcare concern.
- Increasing azole resistance in C. albicans due to prolonged fluconazole therapy necessitates understanding resistance mechanisms.
- Limited effective antifungal agents highlight the urgent need for novel therapeutic strategies.
Purpose of the Study:
- To investigate the gene expression profiles of fluconazole-resistant Candida albicans isolates from bone marrow transplanted patients.
- To identify differentially expressed genes associated with azole resistance in C. albicans.
- To explore potential new drug targets for treating resistant fungal pathogens.
Main Methods:
- Microarray analysis of gene expression in matched fluconazole-susceptible and -resistant C. albicans isolates.
- Validation of differentially expressed genes using reverse transcription-polymerase chain reaction (RT-PCR).
- Identification of specific gene families, including ABC transporters, oxidative stress response, and metal transport genes.
Main Results:
- Over 198 differentially expressed genes were identified between susceptible and resistant C. albicans isolates.
- Increased expression of CDR mRNA and known drug resistance genes (CaIFU5, CaRTA2, CaIFD6) was observed in resistant strains.
- Differential expression of ATP binding cassette (ABC) transporter, oxidative stress, and copper/iron transport genes was noted in resistant isolates.
Conclusions:
- The study elucidates key molecular mechanisms underlying azole resistance in Candida albicans.
- Identified differentially expressed genes, including ABC transporters and stress response genes, represent potential targets for novel antifungal therapies.
- Findings provide insights into the complex genetic basis of antifungal drug resistance and inform clinical treatment strategies.
