The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans.
Constitutive overexpression of the MDR1 (multidrug resistance) gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to fluconazole and other toxic compounds in clinical Candida albicans strains, but the mechanism of MDR1 upregulation has...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2007-11-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.0030164&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850240225659322368 |
|---|---|
| author | Joachim Morschhäuser Katherine S Barker Teresa T Liu Julia BlaB-Warmuth Ramin Homayouni P David Rogers |
| author_facet | Joachim Morschhäuser Katherine S Barker Teresa T Liu Julia BlaB-Warmuth Ramin Homayouni P David Rogers |
| author_sort | Joachim Morschhäuser |
| collection | DOAJ |
| description | Constitutive overexpression of the MDR1 (multidrug resistance) gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to fluconazole and other toxic compounds in clinical Candida albicans strains, but the mechanism of MDR1 upregulation has not been resolved. By genome-wide gene expression analysis we have identified a zinc cluster transcription factor, designated as MRR1 (multidrug resistance regulator), that was coordinately upregulated with MDR1 in drug-resistant, clinical C. albicans isolates. Inactivation of MRR1 in two such drug-resistant isolates abolished both MDR1 expression and multidrug resistance. Sequence analysis of the MRR1 alleles of two matched drug-sensitive and drug-resistant C. albicans isolate pairs showed that the resistant isolates had become homozygous for MRR1 alleles that contained single nucleotide substitutions, resulting in a P683S exchange in one isolate and a G997V substitution in the other isolate. Introduction of these mutated alleles into a drug-susceptible C. albicans strain resulted in constitutive MDR1 overexpression and multidrug resistance. By comparing the transcriptional profiles of drug-resistant C. albicans isolates and mrr1Delta mutants derived from them and of C. albicans strains carrying wild-type and mutated MRR1 alleles, we defined the target genes that are controlled by Mrr1p. Many of the Mrr1p target genes encode oxidoreductases, whose upregulation in fluconazole-resistant isolates may help to prevent cell damage resulting from the generation of toxic molecules in the presence of fluconazole and thereby contribute to drug resistance. The identification of MRR1 as the central regulator of the MDR1 efflux pump and the elucidation of the mutations that have occurred in fluconazole-resistant, clinical C. albicans isolates and result in constitutive activity of this trancription factor provide detailed insights into the molecular basis of multidrug resistance in this important human fungal pathogen. |
| format | Article |
| id | doaj-art-6f392c028ee84fe1b3af281226d49089 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2007-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-6f392c028ee84fe1b3af281226d490892025-08-20T02:00:55ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742007-11-01311e16410.1371/journal.ppat.0030164The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans.Joachim MorschhäuserKatherine S BarkerTeresa T LiuJulia BlaB-WarmuthRamin HomayouniP David RogersConstitutive overexpression of the MDR1 (multidrug resistance) gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to fluconazole and other toxic compounds in clinical Candida albicans strains, but the mechanism of MDR1 upregulation has not been resolved. By genome-wide gene expression analysis we have identified a zinc cluster transcription factor, designated as MRR1 (multidrug resistance regulator), that was coordinately upregulated with MDR1 in drug-resistant, clinical C. albicans isolates. Inactivation of MRR1 in two such drug-resistant isolates abolished both MDR1 expression and multidrug resistance. Sequence analysis of the MRR1 alleles of two matched drug-sensitive and drug-resistant C. albicans isolate pairs showed that the resistant isolates had become homozygous for MRR1 alleles that contained single nucleotide substitutions, resulting in a P683S exchange in one isolate and a G997V substitution in the other isolate. Introduction of these mutated alleles into a drug-susceptible C. albicans strain resulted in constitutive MDR1 overexpression and multidrug resistance. By comparing the transcriptional profiles of drug-resistant C. albicans isolates and mrr1Delta mutants derived from them and of C. albicans strains carrying wild-type and mutated MRR1 alleles, we defined the target genes that are controlled by Mrr1p. Many of the Mrr1p target genes encode oxidoreductases, whose upregulation in fluconazole-resistant isolates may help to prevent cell damage resulting from the generation of toxic molecules in the presence of fluconazole and thereby contribute to drug resistance. The identification of MRR1 as the central regulator of the MDR1 efflux pump and the elucidation of the mutations that have occurred in fluconazole-resistant, clinical C. albicans isolates and result in constitutive activity of this trancription factor provide detailed insights into the molecular basis of multidrug resistance in this important human fungal pathogen.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.0030164&type=printable |
| spellingShingle | Joachim Morschhäuser Katherine S Barker Teresa T Liu Julia BlaB-Warmuth Ramin Homayouni P David Rogers The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathogens |
| title | The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. |
| title_full | The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. |
| title_fullStr | The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. |
| title_full_unstemmed | The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. |
| title_short | The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. |
| title_sort | transcription factor mrr1p controls expression of the mdr1 efflux pump and mediates multidrug resistance in candida albicans |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.0030164&type=printable |
| work_keys_str_mv | AT joachimmorschhauser thetranscriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans AT katherinesbarker thetranscriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans AT teresatliu thetranscriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans AT juliablabwarmuth thetranscriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans AT raminhomayouni thetranscriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans AT pdavidrogers thetranscriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans AT joachimmorschhauser transcriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans AT katherinesbarker transcriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans AT teresatliu transcriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans AT juliablabwarmuth transcriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans AT raminhomayouni transcriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans AT pdavidrogers transcriptionfactormrr1pcontrolsexpressionofthemdr1effluxpumpandmediatesmultidrugresistanceincandidaalbicans |