Disease Information

General Information of the Disease (ID: DIS00041)

• Name: Fungal infection
• ICD: ICD-11: 1F29-1F2F

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Benzoic acid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Polyamine transporter 1 (TPO1) [1]

• Resistant Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Benzoic acid
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Saccharomyces cerevisiae 23344c; 4932
• In Vitro Model: Saccharomyces cerevisiae BY4741; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_gcn4del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_pdr1del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_pdr3del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_pdr8del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_stp1del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_stp2del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_tpo1del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_war1del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_yap1del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_yap2del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_yap3del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_yap4del; 1247190
• In Vitro Model: Saccharomyces cerevisiae BY4741_yap5del; 1247190
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Benzoic acid susceptibility assay
• Mechanism Description: The Saccharomyces cerevisiae multidrug transporter Tpo1 was demonstrated to confer resistance to benzoic acid. TPO1 transcript levels were shown to be up-regulated in yeast cells suddenly exposed to this stress agent. This up-regulation is under the control of the Gcn4 and Stp1 transcription factors, involved in the response to amino acid availability, but not under the regulation of the multidrug resistance transcription factors Pdr1 and Pdr3 that have binding sites in TPO1 promoter.

Cantharidin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Transcription factor PDR1 (PDR1) [2]

• Resistant Disease: Sacharomyces cerevisiae infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cantharidin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: TRAMP-C2 cells; Prostate; Homo sapiens (Human); CVCL_3615
• Experiment for Molecule Alteration: Western blot analysis; Fluorescence microscopy assay
• Experiment for Drug Resistance: Spot dilution assay; Liquid media growth curve analysis; Colony forming unit (CFU) assay
• Mechanism Description: ABC transporter Pdr5 is required for cantharidin resistance in Saccharomyces cerevisiae. Cantharidin mediated upregulation of Pdr5 is majorly regulated by Pdr1, cantharidin induced the upregulation of both PDR1 and PDR5 genes., PDR5 is the main cantharidin resistance gene.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [2]

• Resistant Disease: Sacharomyces cerevisiae infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cantharidin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: TRAMP-C2 cells; Prostate; Homo sapiens (Human); CVCL_3615
• Experiment for Molecule Alteration: Western blot analysis; Fluorescence microscopy assay
• Experiment for Drug Resistance: Spot dilution assay; Liquid media growth curve analysis; Colony forming unit (CFU) assay
• Mechanism Description: ABC transporter Pdr5 is required for cantharidin resistance in Saccharomyces cerevisiae. Cantharidin mediated upregulation of Pdr5 is majorly regulated by Pdr1, cantharidin induced the upregulation of both PDR1 and PDR5 genes., PDR5 is the main cantharidin resistance gene.

Capsaicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [3]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Capsaicin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Saccharomyces cerevisiae S288C; 559292
• In Vitro Model: Yeast deletion strains; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: Capsaicin does not affect the growth rate signicantly but increases the lag period, the addition of capsaicin increased the lag period, especially that of the YOR153W (PDR5, a multi-drug resistance transporter) deletion strain.

Caspofungin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [4]

• Resistant Disease: Saccharomyces cerevisiae infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.F639I
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• Experiment for Molecule Alteration: Site-directed mutagenesis; MLST assay
• Experiment for Drug Resistance: Liquid broth microdilution assay
• Mechanism Description: One group of amino acid substitutions, in the Fks proteins of S. cerevisiae (F639I, V641k, D646Y) and C. albicans (S645F, S645P, S645Y), maps to a short conserved region of ScFks1p and CaFks1p, which lead to caspofungin resistance in the S. cerevisiae and C. albicans as well as C.krusei.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [4]

• Resistant Disease: Saccharomyces cerevisiae infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.V641K
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• Experiment for Molecule Alteration: Site-directed mutagenesis; MLST assay
• Experiment for Drug Resistance: Liquid broth microdilution assay
• Mechanism Description: One group of amino acid substitutions, in the Fks proteins of S. cerevisiae (F639I, V641k, D646Y) and C. albicans (S645F, S645P, S645Y), maps to a short conserved region of ScFks1p and CaFks1p, which lead to caspofungin resistance in the S. cerevisiae and C. albicans as well as C.krusei.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [4]

• Resistant Disease: Saccharomyces cerevisiae infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.D646Y
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• Experiment for Molecule Alteration: Site-directed mutagenesis; MLST assay
• Experiment for Drug Resistance: Liquid broth microdilution assay
• Mechanism Description: One group of amino acid substitutions, in the Fks proteins of S. cerevisiae (F639I, V641k, D646Y) and C. albicans (S645F, S645P, S645Y), maps to a short conserved region of ScFks1p and CaFks1p, which lead to caspofungin resistance in the S. cerevisiae and C. albicans as well as C.krusei.

Chloroquine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Chloroquine resistance transporter (CRT) [5]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.A144T
• Sensitive Drug: Chloroquine
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Saccharomyces cerevisiae BY4741 (MATa his3deta1 leu2deta met15deta ura3deta); 1247190
• In Vitro Model: Saccharomyces cerevisiae CH1305 (MAT a ade2 ade3 ura3 - 52 leu2 lys2 - 801 ); 4932
• In Vitro Model: Saccharomyces cerevisiae detaVma (MATa leu2deta met15deta ura3deta); 4932
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The sequences of PfCRT isoforms 'PH1' and 'PH2', which harbour novel mutations A144T and L160Y. Two isoforms (PH1 and PH2 PfCRT) were found to be intrinsically toxic to yeast, even in the absence.

Key Molecule: Chloroquine resistance transporter (CRT) [5]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.L160Y
• Sensitive Drug: Chloroquine
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Saccharomyces cerevisiae BY4741 (MATa his3deta1 leu2deta met15deta ura3deta); 1247190
• In Vitro Model: Saccharomyces cerevisiae CH1305 (MAT a ade2 ade3 ura3 - 52 leu2 lys2 - 801 ); 4932
• In Vitro Model: Saccharomyces cerevisiae detaVma (MATa leu2deta met15deta ura3deta); 4932
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: The sequences of PfCRT isoforms 'PH1' and 'PH2', which harbour novel mutations A144T and L160Y. Two isoforms (PH1 and PH2 PfCRT) were found to be intrinsically toxic to yeast, even in the absence.

Clotrimazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Resistant Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: Pdr5p is an important ABC transporter. It is a 170 kDa plasma membrane protein with 1511 amino acids in a single polypeptide chain. It effluxes a wide range of structurally and functionally diverse compounds, such as rhodamine 6-G, tetrapropyltin, cycloheximide, tritylimidazole, and clotrimazole. Loss-of-function mutations in the pdr5 gene cause profound drug hypersensitivity, while overexpression creates multidrug hyperresi.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.T257I
• Sensitive Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: The double mutation Gly905Ser/Gly908Ser that is located in the Walker A motif of NBD2. Apparently the double mutation disrupts the ATP catalytic cycle since the cells bearing it are sensitive to all Pdr5p drugs. Other NBD mutations result in a differential sensitivity. Those mutations include Asn242Lys, Thr257Ile, Gly302Asp, Gly1009Cys, Gly1040Asp, Ser1048Val, and His1.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.S1048V
• Sensitive Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: The double mutation Gly905Ser/Gly908Ser that is located in the Walker A motif of NBD2. Apparently the double mutation disrupts the ATP catalytic cycle since the cells bearing it are sensitive to all Pdr5p drugs. Other NBD mutations result in a differential sensitivity. Those mutations include Asn242Lys, Thr257Ile, Gly302Asp, Gly1009Cys, Gly1040Asp, Ser1048Val, and His1.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.N242K
• Sensitive Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: The double mutation Gly905Ser/Gly908Ser that is located in the Walker A motif of NBD2. Apparently the double mutation disrupts the ATP catalytic cycle since the cells bearing it are sensitive to all Pdr5p drugs. Other NBD mutations result in a differential sensitivity. Those mutations include Asn242Lys, Thr257Ile, Gly302Asp, Gly1009Cys, Gly1040Asp, Ser1048Val, and His1.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.H1068A
• Sensitive Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: The double mutation Gly905Ser/Gly908Ser that is located in the Walker A motif of NBD2. Apparently the double mutation disrupts the ATP catalytic cycle since the cells bearing it are sensitive to all Pdr5p drugs. Other NBD mutations result in a differential sensitivity. Those mutations include Asn242Lys, Thr257Ile, Gly302Asp, Gly1009Cys, Gly1040Asp, Ser1048Val, and His1.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.G908S
• Sensitive Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: The double mutation Gly905Ser/Gly908Ser that is located in the Walker A motif of NBD2. Apparently the double mutation disrupts the ATP catalytic cycle since the cells bearing it are sensitive to all Pdr5p drugs. Other NBD mutations result in a differential sensitivity. Those mutations include Asn242Lys, Thr257Ile, Gly302Asp, Gly1009Cys, Gly1040Asp, Ser1048Val, and His1.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.G905S+p.G908S
• Sensitive Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: The double mutation Gly905Ser/Gly908Ser that is located in the Walker A motif of NBD2. Apparently the double mutation disrupts the ATP catalytic cycle since the cells bearing it are sensitive to all Pdr5p drugs. Other NBD mutations result in a differential sensitivity. Those mutations include Asn242Lys, Thr257Ile, Gly302Asp, Gly1009Cys, Gly1040Asp, Ser1048Val, and His1.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.G905S
• Sensitive Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: The double mutation Gly905Ser/Gly908Ser that is located in the Walker A motif of NBD2. Apparently the double mutation disrupts the ATP catalytic cycle since the cells bearing it are sensitive to all Pdr5p drugs. Other NBD mutations result in a differential sensitivity. Those mutations include Asn242Lys, Thr257Ile, Gly302Asp, Gly1009Cys, Gly1040Asp, Ser1048Val, and His1.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.G302D
• Sensitive Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: The double mutation Gly905Ser/Gly908Ser that is located in the Walker A motif of NBD2. Apparently the double mutation disrupts the ATP catalytic cycle since the cells bearing it are sensitive to all Pdr5p drugs. Other NBD mutations result in a differential sensitivity. Those mutations include Asn242Lys, Thr257Ile, Gly302Asp, Gly1009Cys, Gly1040Asp, Ser1048Val, and His1.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.G1040D
• Sensitive Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: The double mutation Gly905Ser/Gly908Ser that is located in the Walker A motif of NBD2. Apparently the double mutation disrupts the ATP catalytic cycle since the cells bearing it are sensitive to all Pdr5p drugs. Other NBD mutations result in a differential sensitivity. Those mutations include Asn242Lys, Thr257Ile, Gly302Asp, Gly1009Cys, Gly1040Asp, Ser1048Val, and His1.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.G1009C
• Sensitive Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: The double mutation Gly905Ser/Gly908Ser that is located in the Walker A motif of NBD2. Apparently the double mutation disrupts the ATP catalytic cycle since the cells bearing it are sensitive to all Pdr5p drugs. Other NBD mutations result in a differential sensitivity. Those mutations include Asn242Lys, Thr257Ile, Gly302Asp, Gly1009Cys, Gly1040Asp, Ser1048Val, and His1.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [6]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.E1289K+p.Y1311S
• Sensitive Drug: Clotrimazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast detapdr5 strain R-1; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determined spectrophotometrically assay
• Mechanism Description: The double mutation Gly905Ser/Gly908Ser that is located in the Walker A motif of NBD2. Apparently the double mutation disrupts the ATP catalytic cycle since the cells bearing it are sensitive to all Pdr5p drugs. Other NBD mutations result in a differential sensitivity. Those mutations include Asn242Lys, Thr257Ile, Gly302Asp, Gly1009Cys, Gly1040Asp, Ser1048Val, and His1.

Lovastatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Transcription factor PDR1 (PDR1) [7]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Lovastatin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Saccharomyces cerevisiae strain Y12409; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y13029; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y13951; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y14381; 4932
• In Vitro Model: Sarcoma tissue; .
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: Spot Test
• Mechanism Description: We investigated the susceptibility to lovastatin of S. cerevisiae strains deleted for PDR genes, responsible for exporting hydrophobic and amphiphilic drugs, such as lovastatin. Strains deleted for the genes tested, PDR1, PDR3, PDR5 and SNQ2, exhibited remarkably different phenotypes, with deletion of PDR5 causing the highest sensitivity to lovastatin. The study helped clarifying which pdr mutants to use in studies of physiological actions of statins in yeast.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs (PDR5) [7]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Lovastatin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Saccharomyces cerevisiae strain Y12409; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y13029; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y13951; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y14381; 4932
• In Vitro Model: Sarcoma tissue; .
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: Spot Test
• Mechanism Description: We investigated the susceptibility to lovastatin of S. cerevisiae strains deleted for PDR genes, responsible for exporting hydrophobic and amphiphilic drugs, such as lovastatin. Strains deleted for the genes tested, PDR1, PDR3, PDR5 and SNQ2, exhibited remarkably different phenotypes, with deletion of PDR5 causing the highest sensitivity to lovastatin. The study helped clarifying which pdr mutants to use in studies of physiological actions of statins in yeast.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transcription factor PDR1 (PDR1) [7]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Lovastatin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Saccharomyces cerevisiae strain Y12409; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y13029; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y13951; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y14381; 4932
• In Vitro Model: Sarcoma tissue; .
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: Spot Test
• Mechanism Description: We investigated the susceptibility to lovastatin of S. cerevisiae strains deleted for PDR genes, responsible for exporting hydrophobic and amphiphilic drugs, such as lovastatin. Strains deleted for the genes tested, PDR1, PDR3, PDR5 and SNQ2, exhibited remarkably different phenotypes, with deletion of PDR5 causing the highest sensitivity to lovastatin. The study helped clarifying which pdr mutants to use in studies of physiological actions of statins in yeast.

Key Molecule: Transcription factor PDR3 (PDR3) [7]

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Lovastatin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Saccharomyces cerevisiae strain Y12409; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y13029; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y13951; 4932
• In Vitro Model: Saccharomyces cerevisiae strain Y14381; 4932
• In Vitro Model: Sarcoma tissue; .
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: Spot Test
• Mechanism Description: We investigated the susceptibility to lovastatin of S. cerevisiae strains deleted for PDR genes, responsible for exporting hydrophobic and amphiphilic drugs, such as lovastatin. Strains deleted for the genes tested, PDR1, PDR3, PDR5 and SNQ2, exhibited remarkably different phenotypes, with deletion of PDR5 causing the highest sensitivity to lovastatin. The study helped clarifying which pdr mutants to use in studies of physiological actions of statins in yeast.

Discontinued Drug(s) 1 drug(s) in total

Arborcandin C

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [8]

• Resistant Disease: Saccharomyces cerevisiae infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.N470K
• Resistant Drug: Arborcandin C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: FkS1 mutations responsible for selective resistance of Saccharomyces cerevisiae to the novel 1,3-beta-glucan synthase inhibitor arborcandin C.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [8]

• Resistant Disease: Saccharomyces cerevisiae infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Missense mutation; p.L642S
• Resistant Drug: Arborcandin C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: FkS1 mutations responsible for selective resistance of Saccharomyces cerevisiae to the novel 1,3-beta-glucan synthase inhibitor arborcandin C.

Investigative Drug(s) 3 drug(s) in total

4-Nitroquinoline N-oxide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Protein SNQ2 (SNQ2) [9]

• Resistant Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: 4-Nitroquinoline N-oxide
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Saccharomyces cerevisiae W303-1A; 580240
• Mechanism Description: The yeast gene SNQ2, which encodes a multidrug resistance ABC superfamily protein, is required for resistance to the mutagen 4-nitroquinoline N-oxide.

Brefeldin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Brefeldin A resistance protein (BFR1) [10]

• Resistant Disease: Schizosaccharomyces pombe infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Brefeldin A
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Schizosaccharomyces pombe BAP1; 4896
• In Vitro Model: Schizosaccharomyces pombe BAP3; 4896
• In Vitro Model: Schizosaccharomyces pombe FWP1; 4896
• Experiment for Molecule Alteration: Northern blot analysis
• Mechanism Description: Here we present the characterization of one of these genes, hba2, which encodes a novel S. pombe protein that shares significant sequence similarity to members of the ATP-binding cassette superfamily of transport proteins. Examination of hba2 expression determined that this gene is overexpressed in mutant strains resistant to brefeldin A due to mutations in the negative regulator crm1 (bar1) gene or the bar2 gene. The increase of hba2 expression was independent of the pap1 transcription factor which is repressed by wild typ.

Hexane-1,6-diol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Sme2 (sme2) [11]

• Resistant Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: .; Expression
• Resistant Drug: Hexane-1,6-diol
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ChIP assay; FISH assay
• Mechanism Description: LncRNA-protein complexes assembled at specific chromosomal loci mediate recognition and subsequent pairing of homologous chromosomes.

Key Molecule: Omt3 (omt3) [11]

• Resistant Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: .; Expression
• Resistant Drug: Hexane-1,6-diol
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ChIP assay; FISH assay
• Mechanism Description: LncRNA-protein complexes assembled at specific chromosomal loci mediate recognition and subsequent pairing of homologous chromosomes.

Key Molecule: Long non-protein coding RNA (LncRNA584) [11]

• Resistant Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: .; Expression
• Resistant Drug: Hexane-1,6-diol
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ChIP assay; FISH assay
• Mechanism Description: LncRNA-protein complexes assembled at specific chromosomal loci mediate recognition and subsequent pairing of homologous chromosomes.

References

• Ref 1: Yeast response and tolerance to benzoic acid involves the Gcn4- and Stp1-regulated multidrug/multixenobiotic resistance transporter Tpo1. Appl Microbiol Biotechnol. 2017 Jun;101(12):5005-5018. doi: 10.1007/s00253-017-8277-6. Epub 2017 Apr 13.
• Ref 2: ABC transporter Pdr5 is required for cantharidin resistance in Saccharomyces cerevisiae .Biochem Biophys Res Commun. 2021 May 14;553:141-147. doi: 10.1016/j.bbrc.2021.03.074. Epub 2021 Mar 24. 10.1016/j.bbrc.2021.03.074
• Ref 3: Studies on the antimicrobial mechanisms of capsaicin using yeast DNA microarray. Biosci Biotechnol Biochem. 2002 Mar;66(3):532-6. doi: 10.1271/bbb.66.532.
• Ref 4: Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother. 2005 Aug;49(8):3264-73. doi: 10.1128/AAC.49.8.3264-3273.2005.
• Ref 5: Plasmodium falciparum chloroquine resistance transporter (PfCRT) isoforms PH1 and PH2 perturb vacuolar physiology. Malar J. 2016 Mar 31;15:186. doi: 10.1186/s12936-016-1238-1.
• Ref 6: Toward understanding the mechanism of action of the yeast multidrug resistance transporter Pdr5p: a molecular modeling study. J Struct Biol. 2011 Feb;173(2):333-44. doi: 10.1016/j.jsb.2010.10.012. Epub 2010 Oct 27.
• Ref 7: Sensitivity to lovastatin of Saccharomyces cerevisiae strains deleted for pleiotropic drug resistance (PDR) genes .J Mol Microbiol Biotechnol. 2011;20(4):191-5. doi: 10.1159/000329068. Epub 2011 Jul 12. 10.1159/000329068
• Ref 8: FKS1 mutations responsible for selective resistance of Saccharomyces cerevisiae to the novel 1,3-beta-glucan synthase inhibitor arborcandin C. Antimicrob Agents Chemother. 2004 Jan;48(1):319-22. doi: 10.1128/AAC.48.1.319-322.2004.
• Ref 9: Functional analysis of the promoter of the yeast SNQ2 gene encoding a multidrug resistance transporter that confers the resistance to 4-nitroquinoline N-oxide. Biosci Biotechnol Biochem. 1999 Jan;63(1):162-7. doi: 10.1271/bbb.63.162.
• Ref 10: Characterization of a novel Schizosaccharomyces pombe multidrug resistance transporter conferring brefeldin A resistance. Biochem Biophys Res Commun. 1995 Aug 15;213(2):410-8. doi: 10.1006/bbrc.1995.2147.
• Ref 11: Chromosome-associated RNA-protein complexes promote pairing of homologous chromosomes during meiosis in Schizosaccharomyces pombeNat Commun. 2019 Dec 6;10(1):5598. doi: 10.1038/s41467-019-13609-0.