Deciphering azole resistance mechanisms with a focus on transcription factor-encoding genes TAC1 , MRR1 and UPC2 in a set of fluconazole-resistant clinical isolates of Candida albicans

• Published in: International journal of antimicrobial agents Vol. 42; no. 5; pp. 410 - 415
• Main Authors: Morio, Florent, Pagniez, Fabrice, Besse, Myriam, Gay-andrieu, Françoise, Miegeville, Michel, Le Pape, Patrice
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2013
• Subjects: Adult; Animals; Antifungal Agents - pharmacology; Azole antifungals; Candida albicans; Candida albicans - drug effects; Candida albicans - genetics; Candida albicans - isolation & purification; Candidiasis - microbiology; Drug Resistance, Fungal; Efflux pumps; Female; Fluconazole - pharmacology; Gene Expression Profiling; Humans; Infectious Disease; Life Sciences; Male; Mice; Microbiology and Parasitology; Middle Aged; Molecular mechanisms; Mutation, Missense; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Santé publique et épidémiologie; Sequence Analysis, DNA; Transcription factors; Transcription Factors - biosynthesis; Transcription Factors - genetics; Candida albicans; Resistance; Efflux pumps; Azole antifungals; Transcription factors; Molecular mechanisms
• ISSN: 0924-8579; 1872-7913; 0924-8579
• DOI: 10.1016/j.ijantimicag.2013.07.013

Abstract Several and often combined mechanisms can lead to acquired azole resistance in Candida albicans and subsequent therapeutic failure. The aim of this study was to provide a complete overview of the molecular basis of azole resistance in a set of six C. albicans clinical isolates recovered from patients who failed azole therapy. For this purpose, expression levels of CDR1 , MDR1 and ERG11 were investigated by reverse transcription PCR (RT-PCR) together with amplification and sequencing of the genes encoding their transcription factors TAC1 , MRR1 and UPC2 . In all, the data underline that azole resistance in this set of clinical isolates results from distinct, often combined, mechanisms, being mostly driven by CDR1 and/or MDR1 active efflux. We show that gain-of-function (GOF) mutations in the transcription-factor-encoding genes TAC1 , MRR1 and UPC2 are a common event in azole-resistant C. albicans clinical isolates. In addition, together with the finding that these genes are highly permissive to nucleotide changes, we describe several novel mutations that could act as putative GOF mutations involved in fluconazole resistance.