RTA2, a novel gene involved in azole resistance in Candida albicans.
Widespread and repeated use of azoles, particularly fluconazole, has led to the rapid development of azole resistance in Candida albicans. Overexpression of CDR1, CDR2, and CaMDR1 has been reported contributing to azole resistance in C. albicans. In this study, hyper-resistant C. albicans mutant, with the above three genes deleted, was obtained by exposure to fluconazole and fluphenezine for 28 passages. Thirty-five differentially expressed genes were identified in the hyper-resistant mutant by microarray analysis; among the 13 up-regulated genes, we successfully constructed the rta2 and ipf14030 null mutants in C. albicans strain with deletions of CDR1, CDR2 and CaMDR1. Using spot dilution assay, we demonstrated that the disruption of RTA2 increased the susceptibility of C. albicans to azoles while the disruption of IPF14030 did not influence the sensitivity of C. albicans to azoles. Meanwhile, we found that ectopic overexpression of RTA2 in C. albicans strain with deletions of CDR1, CDR2 and CaMDR1 conferred resistance to azoles. RTA2 expression was found elevated in clinical azole-resistant isolates of C. albicans. In conclusion, our findings suggest that RTA2 is involved in the development of azole resistance in C. albicans.
Jia
Xin-Ming
XM
Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Ma
Zhi-Ping
ZP
Jia
Yu
Y
Gao
Ping-Hui
PH
Zhang
Jun-Dong
JD
Wang
Yan
Y
Xu
Yong-Gang
YG
Wang
Lin
L
Cao
Ying-Ying
YY
Cao
Yong-Bing
YB
Zhang
Li-Xin
LX
Jiang
Yuan-Ying
YY
D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics; D025141:Drug Resistance, Fungal / Q000235:genetics*; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics / Q000502:physiology*; D005800:Genes, Fungal; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008826:Microbial Sensitivity Tests; D020411:Oligonucleotide Array Sequence Analysis
D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D008565:Membrane Proteins; D015725:Fluconazole