Disease Information

General Information of the Disease (ID: DIS00035)

• Name: Fungal meningitis
• ICD: ICD-11: 1D01

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  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

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [1]

• Resistant Disease: Cryptococcal meningitis [ICD-11: 1D01.0]
• Molecule Alteration: Missense mutation; p.G484S (c.G1855T)
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cryptococcus neoformans stiain CN-5; 5207
• Experiment for Molecule Alteration: Genomic sequence assay
• Experiment for Drug Resistance: Microdilution and E-test methods assay
• Mechanism Description: A point mutation (G1855T) in the ERG11 gene was detected in the FCZ-resistant isolate (CN-5) only. And this mutation is responsible for the amino acid substitution glycine 484 for serine (G484S) in the ERG11 deduced protein sequence of C. neoformans.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter (ABCT) [2]

• Sensitive Disease: Cryptococcal meningitis [ICD-11: 1D01.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluconazole
• 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: We found that the MIC to fluconazole in the knock-out mutant cnafr reduced 16-fold compared to the parent strain BPY22.17, but was nearly equal to that of the matched fluconazole-susceptible strain BPY22 (although was still somewhat less susceptible than strain BPY22).

Itraconazole

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter (ABCT) [2]

• Sensitive Disease: Cryptococcal meningitis [ICD-11: 1D01.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Itraconazole
• 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.

Ketoconazole

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter (ABCT) [2]

• Sensitive Disease: Cryptococcal meningitis [ICD-11: 1D01.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Ketoconazole
• 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.

References

• Ref 1: G484S amino acid substitution in lanosterol 14-alpha demethylase (ERG11) is related to fluconazole resistance in a recurrent Cryptococcus neoformans clinical isolate. Antimicrob Agents Chemother. 2003 Nov;47(11):3653-6. doi: 10.1128/AAC.47.11.3653-3656.2003.
• Ref 2: 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.