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.
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.
Département de Parasitologie et Mycologie Médicale, Université de Nantes, Nantes Atlantique Universités, EA1155-IICiMed, Faculté de Pharmacie, Nantes, France; Laboratoire de Parasitologie-Mycologie, CHU de Nantes, Nantes, France. Electronic address: florent.morio@univ-nantes.fr.
Florent
F
Morio
Fabrice
F
Pagniez
Myriam
M
Besse
Françoise
F
Gay-andrieu
Michel
M
Miegeville
Patrice
P
Le Pape
D000328:Adult; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D002177:Candidiasis / Q000382:microbiology; D025141:Drug Resistance, Fungal; D005260:Female; D015725:Fluconazole / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D000935:Antifungal Agents; D014157:Transcription Factors; D015725:Fluconazole
Azole antifungals; Candida albicans; Efflux pumps; Molecular mechanisms; Resistance; Transcription factors