ABC Transporter Genes Show Upregulated Expression in Drug Resistant Clinical Isolates of Candida auris

a Genome-Wide Characterization of ATP-Binding Cassette (ABC) Transporter Genes

Mohd Wasi, Nitesh K. Khandelwal, Alexander J. Moorhouse, Remya Nair, Poonam Vishwakarma, Gustavo B. Ruiz, Zoe K. Ross, Alexander Lorenz, Shivaprakash M. Rudramurthy, Arunaloke Chakrabarti, Andrew M. Lynn, Alok K. Mondal, Neil A. R. Gow, Rajendra Prasad (Corresponding Author)

Research output: Contribution to journalArticle

Abstract

ATP-binding cassette (ABC) superfamily members have a key role as nutrient importers and exporters in bacteria. However, their role as drug exporters in eukaryotes brought this superfamily member to even greater prominence. The capacity of ABC transporters to efflux a broad spectrum of xenobiotics represents one of the major mechanisms of clinical multidrug resistance in pathogenic fungi including Candida species. Candida auris, a newly emerged multidrug-resistant fungal pathogen of humans that has been responsible for multiple outbreaks of drug-resistant infections in hospitals around the globe. Our study has analyzed the entire complement of ABC superfamily transporters to assess whether these play a major role in drug resistance mechanisms of C. auris. Our bioinformatics analyses identified 28 putative ABC proteins encoded in the genome of the C. auris type-strain CBS 10913T; 20 of which contain transmembrane domains. Quantitative real-time PCR confirmed the expression of all 20 transmembrane domain transporters, underlining their potential in contributing to the C. auris drug resistant phenotype. Changes in transcript levels after short-term exposure of drugs and in drug-resistant C. auris isolates suggested their importance in the drug resistance phenotype of this pathogen. CAUR_02725 orthologous to CDR1, a major multidrug exporter in other yeasts, showed consistently higher expression in multidrug-resistant strains of C. auris. Homologs of other ABC transporter genes, such as CDR4, CDR6 and SNQ2, also displayed raised expression in a sub-set of clinical isolates. Together, our analysis supports the involvement of these transporters in multidrug resistance in C. auris.
Original languageEnglish
Article number1445
Number of pages16
JournalFrontiers in Microbiology
Volume10
Early online date16 Jul 2019
DOIs
Publication statusPublished - 16 Jul 2019

Fingerprint

ATP-Binding Cassette Transporters
Candida
Genome
Pharmaceutical Preparations
Genes
Multiple Drug Resistance
Drug Resistance
Adenosine Triphosphate
Phenotype
Xenobiotics
Cross Infection
Computational Biology
Eukaryota
Disease Outbreaks
Real-Time Polymerase Chain Reaction
Carrier Proteins
Fungi
Yeasts
Bacteria
Food

Keywords

  • Candida auris
  • Multidrug resistance (MDR)
  • ABC proteins
  • drug efflux pumps
  • whole genome sequencing
  • Drug efflux pumps
  • Fluconazole
  • Multidrug resistance
  • multidrug resistance
  • GLABRATA
  • MECHANISM
  • MEMBRANE
  • YEAST
  • fluconazole
  • INVENTORY
  • CLONING
  • ALBICANS
  • PROTEINS
  • STEROL UPTAKE
  • YCF1P

ASJC Scopus subject areas

  • Microbiology (medical)
  • Microbiology

Cite this

ABC Transporter Genes Show Upregulated Expression in Drug Resistant Clinical Isolates of Candida auris : a Genome-Wide Characterization of ATP-Binding Cassette (ABC) Transporter Genes. / Wasi, Mohd; Khandelwal, Nitesh K.; Moorhouse, Alexander J.; Nair, Remya; Vishwakarma, Poonam; Ruiz, Gustavo B.; Ross, Zoe K.; Lorenz, Alexander; Rudramurthy, Shivaprakash M.; Chakrabarti, Arunaloke; Lynn, Andrew M.; Mondal, Alok K.; Gow, Neil A. R.; Prasad, Rajendra (Corresponding Author).

In: Frontiers in Microbiology, Vol. 10, 1445, 16.07.2019.

Research output: Contribution to journalArticle

Wasi, Mohd ; Khandelwal, Nitesh K. ; Moorhouse, Alexander J. ; Nair, Remya ; Vishwakarma, Poonam ; Ruiz, Gustavo B. ; Ross, Zoe K. ; Lorenz, Alexander ; Rudramurthy, Shivaprakash M. ; Chakrabarti, Arunaloke ; Lynn, Andrew M. ; Mondal, Alok K. ; Gow, Neil A. R. ; Prasad, Rajendra. / ABC Transporter Genes Show Upregulated Expression in Drug Resistant Clinical Isolates of Candida auris : a Genome-Wide Characterization of ATP-Binding Cassette (ABC) Transporter Genes. In: Frontiers in Microbiology. 2019 ; Vol. 10.
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abstract = "ATP-binding cassette (ABC) superfamily members have a key role as nutrient importers and exporters in bacteria. However, their role as drug exporters in eukaryotes brought this superfamily member to even greater prominence. The capacity of ABC transporters to efflux a broad spectrum of xenobiotics represents one of the major mechanisms of clinical multidrug resistance in pathogenic fungi including Candida species. Candida auris, a newly emerged multidrug-resistant fungal pathogen of humans that has been responsible for multiple outbreaks of drug-resistant infections in hospitals around the globe. Our study has analyzed the entire complement of ABC superfamily transporters to assess whether these play a major role in drug resistance mechanisms of C. auris. Our bioinformatics analyses identified 28 putative ABC proteins encoded in the genome of the C. auris type-strain CBS 10913T; 20 of which contain transmembrane domains. Quantitative real-time PCR confirmed the expression of all 20 transmembrane domain transporters, underlining their potential in contributing to the C. auris drug resistant phenotype. Changes in transcript levels after short-term exposure of drugs and in drug-resistant C. auris isolates suggested their importance in the drug resistance phenotype of this pathogen. CAUR_02725 orthologous to CDR1, a major multidrug exporter in other yeasts, showed consistently higher expression in multidrug-resistant strains of C. auris. Homologs of other ABC transporter genes, such as CDR4, CDR6 and SNQ2, also displayed raised expression in a sub-set of clinical isolates. Together, our analysis supports the involvement of these transporters in multidrug resistance in C. auris.",
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author = "Mohd Wasi and Khandelwal, {Nitesh K.} and Moorhouse, {Alexander J.} and Remya Nair and Poonam Vishwakarma and Ruiz, {Gustavo B.} and Ross, {Zoe K.} and Alexander Lorenz and Rudramurthy, {Shivaprakash M.} and Arunaloke Chakrabarti and Lynn, {Andrew M.} and Mondal, {Alok K.} and Gow, {Neil A. R.} and Rajendra Prasad",
note = "Funding This work was supported by the ICMR (AMR/149/2018-ECD-II) and DBT (BT/PR14117/BRB/10/1420/2015) to RP. AKM appreciates the support by research grant EMR/2016/001927 and DST PURSE II from the Department of Science and Technology (IN). MW was grateful for a Senior Research Fellowship from the University Grant Commission. NG acknowledges the Wellcome Trust support of a Senior Investigator (101873/Z/13/Z), Collaborative (200208/A/15/Z), and Strategic Awards (097377/Z11/Z), and the MRC Centre for Medical Mycology (MR/N006364/1). AJM was supported by the University of Aberdeen studentship. Work in AL’s laboratory was supported by the Wellcome Trust (212524/Z/18/Z) and the Medical Research Council (MRC) Centre for Medical Mycology at the University of Aberdeen (MR/P501955/1 and MR/N006364/1). Acknowledgments We thank the Centre for Genome Enabled Biology and Medicine at the University of Aberdeen (E. Collie-Duguid and S. Shaw) for sequencing and support with genome analysis.",
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T2 - a Genome-Wide Characterization of ATP-Binding Cassette (ABC) Transporter Genes

AU - Wasi, Mohd

AU - Khandelwal, Nitesh K.

AU - Moorhouse, Alexander J.

AU - Nair, Remya

AU - Vishwakarma, Poonam

AU - Ruiz, Gustavo B.

AU - Ross, Zoe K.

AU - Lorenz, Alexander

AU - Rudramurthy, Shivaprakash M.

AU - Chakrabarti, Arunaloke

AU - Lynn, Andrew M.

AU - Mondal, Alok K.

AU - Gow, Neil A. R.

AU - Prasad, Rajendra

N1 - Funding This work was supported by the ICMR (AMR/149/2018-ECD-II) and DBT (BT/PR14117/BRB/10/1420/2015) to RP. AKM appreciates the support by research grant EMR/2016/001927 and DST PURSE II from the Department of Science and Technology (IN). MW was grateful for a Senior Research Fellowship from the University Grant Commission. NG acknowledges the Wellcome Trust support of a Senior Investigator (101873/Z/13/Z), Collaborative (200208/A/15/Z), and Strategic Awards (097377/Z11/Z), and the MRC Centre for Medical Mycology (MR/N006364/1). AJM was supported by the University of Aberdeen studentship. Work in AL’s laboratory was supported by the Wellcome Trust (212524/Z/18/Z) and the Medical Research Council (MRC) Centre for Medical Mycology at the University of Aberdeen (MR/P501955/1 and MR/N006364/1). Acknowledgments We thank the Centre for Genome Enabled Biology and Medicine at the University of Aberdeen (E. Collie-Duguid and S. Shaw) for sequencing and support with genome analysis.

PY - 2019/7/16

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N2 - ATP-binding cassette (ABC) superfamily members have a key role as nutrient importers and exporters in bacteria. However, their role as drug exporters in eukaryotes brought this superfamily member to even greater prominence. The capacity of ABC transporters to efflux a broad spectrum of xenobiotics represents one of the major mechanisms of clinical multidrug resistance in pathogenic fungi including Candida species. Candida auris, a newly emerged multidrug-resistant fungal pathogen of humans that has been responsible for multiple outbreaks of drug-resistant infections in hospitals around the globe. Our study has analyzed the entire complement of ABC superfamily transporters to assess whether these play a major role in drug resistance mechanisms of C. auris. Our bioinformatics analyses identified 28 putative ABC proteins encoded in the genome of the C. auris type-strain CBS 10913T; 20 of which contain transmembrane domains. Quantitative real-time PCR confirmed the expression of all 20 transmembrane domain transporters, underlining their potential in contributing to the C. auris drug resistant phenotype. Changes in transcript levels after short-term exposure of drugs and in drug-resistant C. auris isolates suggested their importance in the drug resistance phenotype of this pathogen. CAUR_02725 orthologous to CDR1, a major multidrug exporter in other yeasts, showed consistently higher expression in multidrug-resistant strains of C. auris. Homologs of other ABC transporter genes, such as CDR4, CDR6 and SNQ2, also displayed raised expression in a sub-set of clinical isolates. Together, our analysis supports the involvement of these transporters in multidrug resistance in C. auris.

AB - ATP-binding cassette (ABC) superfamily members have a key role as nutrient importers and exporters in bacteria. However, their role as drug exporters in eukaryotes brought this superfamily member to even greater prominence. The capacity of ABC transporters to efflux a broad spectrum of xenobiotics represents one of the major mechanisms of clinical multidrug resistance in pathogenic fungi including Candida species. Candida auris, a newly emerged multidrug-resistant fungal pathogen of humans that has been responsible for multiple outbreaks of drug-resistant infections in hospitals around the globe. Our study has analyzed the entire complement of ABC superfamily transporters to assess whether these play a major role in drug resistance mechanisms of C. auris. Our bioinformatics analyses identified 28 putative ABC proteins encoded in the genome of the C. auris type-strain CBS 10913T; 20 of which contain transmembrane domains. Quantitative real-time PCR confirmed the expression of all 20 transmembrane domain transporters, underlining their potential in contributing to the C. auris drug resistant phenotype. Changes in transcript levels after short-term exposure of drugs and in drug-resistant C. auris isolates suggested their importance in the drug resistance phenotype of this pathogen. CAUR_02725 orthologous to CDR1, a major multidrug exporter in other yeasts, showed consistently higher expression in multidrug-resistant strains of C. auris. Homologs of other ABC transporter genes, such as CDR4, CDR6 and SNQ2, also displayed raised expression in a sub-set of clinical isolates. Together, our analysis supports the involvement of these transporters in multidrug resistance in C. auris.

KW - Candida auris

KW - Multidrug resistance (MDR)

KW - ABC proteins

KW - drug efflux pumps

KW - whole genome sequencing

KW - Drug efflux pumps

KW - Fluconazole

KW - Multidrug resistance

KW - multidrug resistance

KW - GLABRATA

KW - MECHANISM

KW - MEMBRANE

KW - YEAST

KW - fluconazole

KW - INVENTORY

KW - CLONING

KW - ALBICANS

KW - PROTEINS

KW - STEROL UPTAKE

KW - YCF1P

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DO - 10.3389/fmicb.2019.01445

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JO - Frontiers in Microbiology

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