Drug Information

Drug (ID: DG00147) and It's Reported Resistant Information

• Name: Ketoconazole
• Synonyms: KCZ; KTZ; K 1003; R 41400; R41400; KS-1205; KW-1414; Perkhotal (TN); R 41,400; R-41400; R41,400; Ketoconazole [USAN:INN:BAN:JAN]; Nizoral, Extina, Xolegel, Kuric, Ketoconazole; Dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-piperazine; Cis-1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine; CIS-1-ACETYL-4-(4-((2-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YLMETHYL)-1,3-DIOXOLAN-4-YL)METHOXY)PHENYL)PIPERAZINE; (+-)-cis-1-Acetyl-4-(p-((2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazine; (+/-)-cis-1-Acetyl-4-(4-[(2-[2,4-dichlorophenyl]-2-[1H-imidazol-1-ylmethyl]-1,3-dioxolan-4-yl)-methoxy]phenyl)piperazine; (+/-)-cis-1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine; 1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone; 1-acetyl-4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine
• Indication:
  In total 1 Indication(s)
  Fungal infection [ICD-11: 1F29-1F2F]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Candidosis [ICD-11: 1F23]; [2]
• Target: Candida Cytochrome P450 51 (Candi ERG11); CP51_CANAL; [1]
• Formula: C26H28Cl2N4O4
• IsoSMILES: CC(=O)N1CCN(CC1)C2=CC=C(C=C2)OC[C@H]3CO[C@](O3)(CN4C=CN=C4)C5=C(C=C(C=C5)Cl)Cl
• InChI: 1S/C26H28Cl2N4O4/c1-19(33)31-10-12-32(13-11-31)21-3-5-22(6-4-21)34-15-23-16-35-26(36-23,17-30-9-8-29-18-30)24-7-2-20(27)14-25(24)28/h2-9,14,18,23H,10-13,15-17H2,1H3/t23-,26-/m0/s1
• InChIKey: XMAYWYJOQHXEEK-OZXSUGGESA-N
• PubChem CID: 456201
• ChEBI ID: CHEBI:48336
• TTD Drug ID: D0B4IF
• DrugBank ID: DB01026

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Fungal meningitis [ICD-11: 1D01]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter (ABCT) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cryptococcal meningitis [ICD-11: 1D01.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cryptococcus neoformans stiain BPY22.17; 5207
• Experiment for Molecule Alteration: Southern hybridization analysis; Northern hybridization analysis
• Experiment for Drug Resistance: Rhodamine 6G accumulation assay; M27-A assay
• Mechanism Description: Again, disruption of CnAFR1 gene resulted in an increased susceptibility to ketoconazole and itraconazole, suggesting that these antifungal azoles are substrates for CnAfr1p.

Candidosis [ICD-11: 1F23]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [2]

• Molecule Alteration: Missense mutation; p.Y132H
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [2]

• Molecule Alteration: Missense mutation; p.S405F+p.Y132H
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [2]

• Molecule Alteration: Missense mutation; p.G464S+p.Y132H
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [2]

• Molecule Alteration: Missense mutation; p.G464S+p.R467K
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [2]

• Molecule Alteration: Missense mutation; p.G464S+p.G129A
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

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 CDR1 (CDR1) [3]

• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tethering factor for nuclear proteasome STS1 (STS1) [4]

• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• Experiment for Molecule Alteration: qPCR; TEF3 probe assay
• Experiment for Drug Resistance: Microbroth dilution MIC assay
• Mechanism Description: The S. cerevisiae sts1 deletion mutant was hypersusceptible to all three azole derivatives used in the study, which is a strong indication that Sts1, a close homolog of Cdr1, is implicated in their transport.

References

• Ref 1: Identification and characterization of a Cryptococcus neoformans ATP binding cassette (ABC) transporter-encoding gene, CnAFR1, involved in the resistance to fluconazole. Mol Microbiol. 2003 Jan;47(2):357-71. doi: 10.1046/j.1365-2958.2003.03281.x.
• Ref 2: Amino acid substitutions in the cytochrome P-450 lanosterol 14alpha-demethylase (CYP51A1) from azole-resistant Candida albicans clinical isolates contribute to resistance to azole antifungal agents. Antimicrob Agents Chemother. 1998 Feb;42(2):241-53. doi: 10.1128/AAC.42.2.241.
• Ref 3: 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 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.