Molecule Information

General Information of the Molecule (ID: Mol01049)

• Name: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) ,Candida albicans
• Synonyms: Pleiotropic drug resistance protein CDR1; CAALFM_C305220WA; CaO19.13421; CaO19.6000
• Molecule Type: Protein
• Gene Name: CDR1
• Gene ID: 3635237
• Sequence:
  MSDSKMSSQDESKLEKAISQDSSSENHSINEYHGFDAHTSENIQNLARTFTHDSFKDDSS
  AGLLKYLTHMSEVPGVNPYEHEEINNDQLNPDSENFNAKFWVKNLRKLFESDPEYYKPSK
  LGIGYRNLRAYGVANDSDYQPTVTNALWKLATEGFRHFQKDDDSRYFDILKSMDAIMRPG
  ELTVVLGRPGAGCSTLLKTIAVNTYGFHIGKESQITYDGLSPHDIERHYRGDVIYSAETD
  VHFPHLSVGDTLEFAARLRTPQNRGEGIDRETYAKHMASVYMATYGLSHTRNTNVGNDFV
  RGVSGGERKRVSIAEASLSGANIQCWDNATRGLDSATALEFIRALKTSAVILDTTPLIAI
  YQCSQDAYDLFDKVVVLYEGYQIFFGKATKAKEYFEKMGWKCPQRQTTADFLTSLTNPAE
  REPLPGYEDKVPRTAQEFETYWKNSPEYAELTKEIDEYFVECERSNTRETYRESHVAKQS
  NNTRPASPYTVSFFMQVRYGVARNFLRMKGDPSIPIFSVFGQLVMGLILSSVFYNLSQTT
  GSFYYRGAAMFFAVLFNAFSSLLEIMSLFEARPIVEKHKKYALYRPSADALASIISELPV
  KLAMSMSFNFVFYFMVNFRRNPGRFFFYWLMCIWCTFVMSHLFRSIGAVSTSISGAMTPA
  TVLLLAMVIYTGFVIPTPSMLGWSRWINYINPVGYVFESLMVNEFHGREFQCAQYVPSGP
  GYENISRSNQVCTAVGSVPGNEMVSGTNYLAGAYQYYNSHKWRNLGITIGFAVFFLAIYI
  ALTEFNKGAMQKGEIVLFLKGSLKKHKRKTAASNKGDIEAGPVAGKLDYQDEAEAVNNEK
  FTEKGSTGSVDFPENREIFFWRDLTYQVKIKKEDRVILDHVDGWVKPGQITALMGASGAG
  KTTLLNCLSERVTTGIITDGERLVNGHALDSSFQRSIGYVQQQDVHLETTTVREALQFSA
  YLRQSNKISKKEKDDYVDYVIDLLEMTDYADALVGVAGEGLNVEQRKRLTIGVELVAKPK
  LLLFLDEPTSGLDSQTAWSICKLMRKLADHGQAILCTIHQPSALIMAEFDRLLFLQKGGR
  TAYFGELGENCQTMINYFEKYGADPCPKEANPAEWMLQVVGAAPGSHAKQDYFEVWRNSS
  EYQAVREEINRMEAELSKLPRDNDPEALLKYAAPLWKQYLLVSWRTIVQDWRSPGYIYSK
  IFLVVSAALFNGFSFFKAKNNMQGLQNQMFSVFMFFIPFNTLVQQMLPYFVKQRDVYEVR
  EAPSRTFSWFAFIAGQITSEIPYQVAVGTIAFFCWYYPLGLYNNATPTDSVNPRGVLMWM
  LVTAFYVYTATMGQLCMSFSELADNAANLATLLFTMCLNFCGVLAGPDVLPGFWIFMYRC
  NPFTYLVQAMLSTGLANTFVKCAEREYVSVKPPNGESCSTYLDPYIKFAGGYFETRNDGS
  CAFCQMSSTNTFLKSVNSLYSERWRNFGIFIAFIAINIILTVIFYWLARVPKGNREKKNK
  K
• Function: Pleiotropic ABC efflux transporter that confers resistance to numerous chemicals including anisomycin, cycloheximide, fluconazole, miconazole, ketoconazole, itriconazole, nystatin, terbinafine, amorolfine, brefeldin A, amphotericin B, fluphenazine, as well as estrogen. Plays a role in farnesol-induced apoptotic process through glutathione efflux activity. Mediates in-to-out translocation of membrane phospholipids including aminophospholipids and thus regulates asymmetric distribution of phosphatidylethanolamine. Exhibits nucleoside triphosphatase activity.
• Uniprot ID: CDR1_CANAL

Kingdom: Fungi
Phylum: Ascomycota
Class: Saccharomycetes
Order: Saccharomycetales
Family: Debaryomycetaceae
Genus: Candida
Species: Candida albicans

Type(s) of Resistant Mechanism of This Molecule

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

Approved Drug(s) 7 drug(s) in total

Amorolfine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Sensitive Drug: Amorolfine
• Molecule Alteration: Deletion mutation; Deleteion
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine).

Fluconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Candidosis [2]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Overexpression of the genes ERG11, CDR1, CDR2, MDR1, and FLU1 has been linked to fluconazole resistance (White et al., 1998) and was investigated as a mechanism of resistance in our clinical isolates by using real-time RT-PCR.

Disease Class: Mycotic vaginitis [3]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Recurrent oropharyngeal candidiasis [4]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: qPCR; TEF3 probe assay
• Experiment for Drug Resistance: Microbroth dilution MIC assay
• Mechanism Description: Failure in accumulating this compound among resistant yeast cells can be related to at least two phenomenona: a significant increase in the level of CDR1 mRNA and a corresponding increase in the level of BENr mRNA. CDR1 and BENr are both multidrug transporter genes, each belonging to distinct classes of transporters.

Disease Class: Recurrent oropharyngeal candidiasis [5], [6], [7]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: The genes coding for several ABC transporters in C. albicans have been identified, including several CDR genes (19, 26). CDR1 and CDR2 were the first two members of this family identified in C. albicans, and both CDR1 and CDR2 have been described as playing a role in fluconazole resistance.

Disease Class: Recurrent oropharyngeal candidiasis [8]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: In C. albicans, overexpression of two homologous ABC transporters, Cdr1 and Cdr2, have been frequently implicated in azole resistance, particularly in patients receiving long-term antifungal therapy.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Sensitive Drug: Fluconazole
• Molecule Alteration: Deletion mutation; Deleteion
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 C. albicans mutant DSY448 was hypersusceptible to the azole derivatives fluconazole, itraconazole, and ketoconazole, thus showing that the ABC transporter Cdr1 can use these compounds as substrates. And this could be attributed to a less efficient fluconazole efflux activity because of the absence of the ABC transporter Cdr1 in the delta cdr1 mutant.

Fluphenazine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Sensitive Drug: Fluphenazine
• Molecule Alteration: Deletion mutation; Deleteion
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine).

Gentian violet

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Sensitive Drug: Gentian violet
• Molecule Alteration: Deletion mutation; Deleteion
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was slightly more susceptible than the wild type to nocodazole, cerulenin, and crystal violet but not to amphotericin B, nikkomy- cin Z, flucytosine, or pradimicin.

Itraconazole

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Sensitive Drug: Itraconazole
• Molecule Alteration: Deletion mutation; Deleteion
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 C. albicans mutant DSY448 was hypersusceptible to the azole derivatives fluconazole, itraconazole, and ketoconazole, thus showing that the ABC transporter Cdr1 can use these compounds as substrates. And this could be attributed to a less efficient fluconazole efflux activity because of the absence of the ABC transporter Cdr1 in the delta cdr1 mutant.

Ketoconazole

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Sensitive Drug: Ketoconazole
• Molecule Alteration: Deletion mutation; Deleteion
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 C. albicans mutant DSY448 was hypersusceptible to the azole derivatives fluconazole, itraconazole, and ketoconazole, thus showing that the ABC transporter Cdr1 can use these compounds as substrates. And this could be attributed to a less efficient fluconazole efflux activity because of the absence of the ABC transporter Cdr1 in the delta cdr1 mutant.

Terbinafine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Sensitive Drug: Terbinafine
• Molecule Alteration: Deletion mutation; Deleteion
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine).

Investigative Drug(s) 4 drug(s) in total

Brefeldin A

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Sensitive Drug: Brefeldin A
• Molecule Alteration: Deletion mutation; Deleteion
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine).

Cerulenin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Sensitive Drug: Cerulenin
• Molecule Alteration: Deletion mutation; Deleteion
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was slightly more susceptible than the wild type to nocodazole, cerulenin, and crystal violet but not to amphotericin B, nikkomy- cin Z, flucytosine, or pradimicin.

Cycloheximide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Sensitive Drug: Cycloheximide
• Molecule Alteration: Deletion mutation; Deleteion
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine).

Nocodazole

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Sensitive Drug: Nocodazole
• Molecule Alteration: Deletion mutation; Deleteion
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was slightly more susceptible than the wild type to nocodazole, cerulenin, and crystal violet but not to amphotericin B, nikkomy- cin Z, flucytosine, or pradimicin.

References

• Ref 1: Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. Antimicrob Agents Chemother. 1996 Oct;40(10):2300-5. doi: 10.1128/AAC.40.10.2300.
• Ref 2: Evaluation of fluconazole resistance mechanisms in candida albicans clinical isolates from HIV-infected patients in Brazil. Diagn Microbiol Infect Dis. 2004 Sep;50(1):25-32. doi: 10.1016/j.diagmicrobio.2004.04.009.
• Ref 3: Resistance mechanisms in fluconazole-resistant Candida albicans isolates from vaginal candidiasis. Int J Antimicrob Agents. 2006 May;27(5):403-8. doi: 10.1016/j.ijantimicag.2005.12.005. Epub 2006 Apr 18.
• Ref 4: Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob Agents Chemother. 1995 Nov;39(11):2378-86. doi: 10.1128/AAC.39.11.2378.
• Ref 5: Multiple resistant phenotypes of Candida albicans coexist during episodes of oropharyngeal candidiasis in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 1999 Jul;43(7):1621-30. doi: 10.1128/AAC.43.7.1621.
• Ref 6: Application of real-time quantitative PCR to molecular analysis of Candida albicans strains exhibiting reduced susceptibility to azoles. Antimicrob Agents Chemother. 2004 Jun;48(6):2124-31. doi: 10.1128/AAC.48.6.2124-2131.2004.
• Ref 7: Analysis of a Candida albicans gene that encodes a novel mechanism for resistance to benomyl and methotrexate. Mol Gen Genet. 1991 Jun;227(2):318-29. doi: 10.1007/BF00259685.
• Ref 8: Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond .Chem Rev. 2021 Mar 24;121(6):3390-3411. doi: 10.1021/acs.chemrev.0c00199. Epub 2020 May 22. 10.1021/acs.chemrev.0c00199