cDNA microarray analysis of differential gene expression and regulation in clinically drug-resistant isolates of Candida albicans from bone marrow transplanted patients.
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.
Xu
Zheng
Z
Department of Pharmacology, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, PR China.
Zhang
Li-Xin
LX
Zhang
Jun-Dong
JD
Cao
Yong-Bing
YB
Yu
Yuan-Yuan
YY
Wang
De-Jun
DJ
Ying
Kang
K
Chen
Wan-Sheng
WS
Jiang
Yuan-Ying
YY
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000935:Antifungal Agents / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics*; D002177:Candidiasis / Q000382:microbiology; D003300:Copper / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000235:genetics*; D015725:Fluconazole / Q000494:pharmacology; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D007501:Iron / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D003300:Copper; D015725:Fluconazole; D007501:Iron