Molecule Information

General Information of the Molecule (ID: Mol01011)

• Name: Multidrug resistance protein 1 (ABCB1) ,Candida albicans
• Synonyms: Benomyl resistance protein 1; BEN; BMR1; CAALFM_C603170CA; CaO19.13047; CaO19.5604
• Molecule Type: Protein
• Gene Name: MDR1
• Gene ID: 3639260
• Sequence:
  MHYRFLRDSFVGRVTYHLSKHKYFAHPEEAKDYIVPEKYLADYKPTLADDTSINFEKEEI
  DNQGEPNSSQSSSSNNTIVDNNNNNDNDVDGDKIVVTWDGDDDPENPQNWPTLQKAFFIF
  QISFLTTSVYMGSAVYTPGIEELMHDFGIGRVVATLPLTLFVIGYGVGPLVFSPMSENAI
  FGRTSIYIITLFLFVILQIPTALVNNIAGLCILRFLGGFFASPCLATGGASVADVVKFWN
  LPVGLAAWSLGAVCGPSFGPFFGSILTVKASWRWTFWFMCIISGFSFVMLCFTLPETFGK
  TLLYRKAKRLRAITGNDRITSEGEVENSKMTSHELIIDTLWRPLEITVMEPVVLLINIYI
  AMVYSILYLFFEVFPIYFVGVKHFTLVELGTTYMSIVIGIVIAAFIYIPVIRQKFTKPIL
  RQEQVFPEVFIPIAIVGGILLTSGLFIFGWSANRTTHWVGPLFGAATTASGAFLIFQTLF
  NFMGASFKPHYIASVFASNDLFRSVIASVFPLFGAPLFDNLATPEYPVAWGSSVLGFITL
  VMIAIPVLFYLNGPKLRARSKYAN
• Function: Plasma membrane multidrug efflux pump that confers resistance to numerous chemicals including azoles such as fluconazole, voriconazole, and benztriazoles, as well as to benomyl, cycloheximide, methotrexate, 4-nitroquinoline-N-oxide, sulfometuron methyl, cerulenin, and brefeldin A.
• Uniprot ID: MDR1_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) 3 drug(s) in total

Fluconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Candidosis [1]

• 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 [2]

• 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 [3]

• 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 [4], [5], [6]

• 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: A second major mechanism is through increased efflux of drug, mediated by two types of multidrug efflux pumps, the major facilitators and the ABC transporters. The MDR1 gene encodes a major facilitator implicated in resistance, and its overexpression leads to fluconazole resistance exclusively among azole drugs.

Disease Class: Recurrent oropharyngeal candidiasis [7]

• 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: Although 95 MF transporters are encoded in the C. albicans genome, fluconazole resistance has only been linked to Mdr1 (multidrug resistance 1). Expression of this MF pump is regulated by the transcription factor, Mrr1 (multidrug resistance regulator 1), such that deletion of MRR1 abolishes MDR1 expression and increases susceptibility to fluconazole, whereas activating point mutations in MRR1 increase azole resistance.

Itraconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Mycotic vaginitis [2]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Itraconazole
• 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.

Voriconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Mycotic vaginitis [2]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Voriconazole
• 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.

References

• Ref 1: 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 2: 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 3: 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 4: 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 5: 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 6: Mutation in cytochrome P-450-dependent 14 alpha-demethylase results in decreased affinity for azole antifungals. Biochem Soc Trans. 1990 Feb;18(1):56-9. doi: 10.1042/bst0180056.
• Ref 7: 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