Drug Information

Drug (ID: DG00084) and It's Reported Resistant Information

• Name: Posaconazole
• Synonyms: Noxafil; Spriafil; Posaconazole SP; Posaconazole in combination with MGCD290; SCH56592; Sch 56592; X2N; Noxafil (TN); Noxafil, Posaconazole; SCH-56592; Posaconazole (USAN/INN); Posaconazole [USAN:INN:BAN]; 1-((1S,2S)-1-Ethyl-2-hydroxypropyl)-4-{4-[4-(4-{[(5S,3R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazolylmethyl)oxolan-3-yl]methoxy}phenyl)piperazinyl]phenyl}-1,2,4-triazolin-5-one; 4-(p-(4-(p-(((3R,5R)-5-(2,4-Difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furyl)methoxy)phenyl)-1-piperazinyl)phenyl)-1-((1S,2S)-1-ethyl-2-hydroxypropyl)-delta(sup 2)-1,2,4-triazolin-5-one; 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one; 4-[4-[4-[4-[[(5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one
• Indication:
  In total 1 Indication(s)
  Aspergillosis [ICD-11: 1F20]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Aspergillosis [ICD-11: 1F20]; [2]
  Candidosis [ICD-11: 1F23]; [3]
• Target: Candida Cytochrome P450 51 (Candi ERG11); CP51_CANAL; [1]
• Formula: C37H42F2N8O4
• IsoSMILES: CC[C@@H]([C@H](C)O)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OC[C@H]5C[C@](OC5)(CN6C=NC=N6)C7=C(C=C(C=C7)F)F
• InChI: 1S/C37H42F2N8O4/c1-3-35(26(2)48)47-36(49)46(25-42-47)31-7-5-29(6-8-31)43-14-16-44(17-15-43)30-9-11-32(12-10-30)50-20-27-19-37(51-21-27,22-45-24-40-23-41-45)33-13-4-28(38)18-34(33)39/h4-13,18,23-27,35,48H,3,14-17,19-22H2,1-2H3/t26-,27+,35-,37-/m0/s1
• InChIKey: RAGOYPUPXAKGKH-XAKZXMRKSA-N
• PubChem CID: 468595
• ChEBI ID: CHEBI:64355
• TTD Drug ID: D07ABV
• VARIDT ID: DR00111
• INTEDE ID: DR1316
• DrugBank ID: DB01263

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Aspergillosis [ICD-11: 1F20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [1]

• Molecule Alteration: Missense mutation; p.F46Y+p.M172V+p.N248T+p.D255E
• Resistant Disease: Aspergillus fumigatus infection [ICD-11: 1F20.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: EUCAST broth dilution method assay
• Mechanism Description: Interestingly, the F46Y/M172V/N248T/D255E/E427k mutation, which has been reported to be associated with azole resistance (37), was detected in one clinical isolate from Shanghai and in one environmental isolate from Xinjiang, respectively.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [2]

• Molecule Alteration: Missense mutation; p.G54W
• Resistant Disease: Aspergillus fumigatus infection [ICD-11: 1F20.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: In the four isolates exhibiting moderate levels of POS resistance glycine 54 was mutated to either glutamate or arginine. In the mutant with a high level of POS resistance glycine 54 was mutated to tryptophan.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [4]

• Molecule Alteration: Missense mutation; p.G138C
• Resistant Disease: Aspergillus fumigatus infection [ICD-11: 1F20.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Each single mutationad a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [5]

• Molecule Alteration: Missense mutation; p.G54E
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain RIT; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS M38-P microdilution methodology assay
• Mechanism Description: Itraconazole resistance has been tightly linked to cyp51A mutations in the codon for Gly54, resulting in five different amino substitutions (G54k, G54V, G54R, G54E, and G54W).

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [5]

• Molecule Alteration: Missense mutation; p.G54K
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain RIT; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS M38-P microdilution methodology assay
• Mechanism Description: The G54k amino acid change conferred cross-resistance to both itraconazole and posaconazole (26). The replacement of the wild-type chromosomal cyp51A allele by mutant allele bearing the G161A nucleotide change in codon 54 led to the acquisition of resistance to itraconazole de novo.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [6]

• Molecule Alteration: Missense mutation; p.R228Q
• Resistant Disease: Aspergillus niger infection [ICD-11: 1F20.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus niger strain; 5061
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging posaconazole resistance.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [7]

• Molecule Alteration: Missense mutation; p.P216L
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: EUCAST method assay
• Mechanism Description: Four novel mutations were found (H147Y, P216L, Y431C, and G434C). The isolate bearing the P216L mutation was resistant to itraconazole and posaconazole, whereas the isolates with Y431C and G434C showed pan-azole resistance phenotypes.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [7]

• Molecule Alteration: Missense mutation; p.G434C
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: EUCAST method assay
• Mechanism Description: Four novel mutations were found (H147Y, P216L, Y431C, and G434C). The isolate bearing the P216L mutation was resistant to itraconazole and posaconazole, whereas the isolates with Y431C and G434C showed pan-azole resistance phenotypes.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [7]

• Molecule Alteration: Missense mutation; p.Y431C
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: EUCAST method assay
• Mechanism Description: Four novel mutations were found (H147Y, P216L, Y431C, and G434C). The isolate bearing the P216L mutation was resistant to itraconazole and posaconazole, whereas the isolates with Y431C and G434C showed pan-azole resistance phenotypes.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [8]

• Molecule Alteration: Missense mutation; p.Y121F+p.T289A+p.G448S+p.M172I
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain TR463; 746128
• Experiment for Molecule Alteration: PCR analysis
• Mechanism Description: In addition, to compare the susceptibility of TR463 with those of TR34 and TR46, the high resistance of TR463/Y121F/M172I/T289A/G448S was confirmed by MIC testing, displaying a pan-triazole-resistant phenotype to posaconazole, itraconazole, and voriconazole, indicating no in vitro activity of itraconazole and voriconazole (MIC, >16 mg/liter).

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) [3]

• Molecule Alteration: Missense mutation; p.Y132F
• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Overall, among 45% (n = 20) of isolates that had Y132F and k143R substitutions, 16 showed cross-resistance to one or more azoles namely voriconazole, isavuconazole and posaconazole and four were pan-azole resistant.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [3]

• Molecule Alteration: Missense mutation; p.K143R
• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Overall, among 45% (n = 20) of isolates that had Y132F and k143R substitutions, 16 showed cross-resistance to one or more azoles namely voriconazole, isavuconazole and posaconazole and four were pan-azole resistant.

References

• Ref 1: Epidemiology and Molecular Characterizations of Azole Resistance in Clinical and Environmental Aspergillus fumigatus Isolates from China. Antimicrob Agents Chemother. 2016 Sep 23;60(10):5878-84. doi: 10.1128/AAC.01005-16. Print 2016 Oct.
• Ref 2: Mutations in Aspergillus fumigatus resulting in reduced susceptibility to posaconazole appear to be restricted to a single amino acid in the cytochrome P450 14alpha-demethylase. Antimicrob Agents Chemother. 2003 Feb;47(2):577-81. doi: 10.1128/AAC.47.2.577-581.2003.
• Ref 3: A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009-17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J Antimicrob Chemother. 2018 Apr 1;73(4):891-899. doi: 10.1093/jac/dkx480.
• Ref 4: Proposal for a unified nomenclature for target-site mutations associated with resistance to fungicides. Pest Manag Sci. 2016 Aug;72(8):1449-59. doi: 10.1002/ps.4301. Epub 2016 Jun 16.
• Ref 5: Rapid, high-throughput, multiplex, real-time PCR for identification of mutations in the cyp51A gene of Aspergillus fumigatus that confer resistance to itraconazole. J Clin Microbiol. 2005 Jan;43(1):214-22. doi: 10.1128/JCM.43.1.214-222.2005.
• Ref 6: Species Distribution and In Vitro Azole Susceptibility of Aspergillus Section Nigri Isolates from Clinical and Environmental Settings. J Clin Microbiol. 2016 Sep;54(9):2365-72. doi: 10.1128/JCM.01075-16. Epub 2016 Jul 13.
• Ref 7: Frequency and evolution of Azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg Infect Dis. 2009 Jul;15(7):1068-76. doi: 10.3201/eid1507.090043.
• Ref 8: A Novel Environmental Azole Resistance Mutation in Aspergillus fumigatus and a Possible Role of Sexual Reproduction in Its Emergence. mBio. 2017 Jun 27;8(3):e00791-17. doi: 10.1128/mBio.00791-17.