Drug Information

Drug (ID: DG00060) and It's Reported Resistant Information

• Name: Pyrimethamine/Sulfadoxine
• Synonyms: Fansidar; Suldox; Pyrimethamine-sulfadoxine; 37338-39-9; Pyrimethamine mixture with sulfadoxine; Pyrimethamine combination with sulfadoxine; Benzenesulfonamide, 4-amino-N-(5,6-dimethoxy-4-pyrimidinyl)-, mixt. with 5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine; sulphadoxine-pyrimethamine; sulfadoxine/pyrimethamine; Sulphadoxyne-pyrimethamine; sulfadoxine / pyrimethamine; Pyrimethamine / sulfadoxine; Sulphadoxine / pyrimethamine; Pyrimethamine-sulfadoxine mixt.; Sulfadoxine-pyrimethamine mixt.; Fansidar (TN)
• Indication:
  In total 1 Indication(s)
  Pneumonia [ICD-11: CA40]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Plasmodium vivax malaria [ICD-11: 1F41]; [2]
  Pneumonia [ICD-11: CA40]; [3]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Astrocytoma [ICD-11: 2F36]; [1]
• Formula: C24H27ClN8O4S
• IsoSMILES: CCC1=C(C(=NC(=N1)N)N)C2=CC=C(C=C2)Cl.COC1=C(N=CN=C1OC)NS(=O)(=O)C2=CC=C(C=C2)N
• InChI: 1S/C12H13ClN4.C12H14N4O4S/c1-2-9-10(11(14)17-12(15)16-9)7-3-5-8(13)6-4-7;1-19-10-11(14-7-15-12(10)20-2)16-21(17,18)9-5-3-8(13)4-6-9/h3-6H,2H2,1H3,(H4,14,15,16,17);3-7H,13H2,1-2H3,(H,14,15,16)
• InChIKey: LUBUTTBEBGYNJN-UHFFFAOYSA-N
• PubChem CID: 65404
• TTD Drug ID: D04UZN

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

Plasmodium vivax malaria [ICD-11: 1F41]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Bifunctional dihydrofolate reductase-thymidylate synthase (PVDHFR) [2]

• Molecule Alteration: SNP; .
• Resistant Disease: Plasmodium vivax malaria [ICD-11: 1F41.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Red blood cells; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: Giemsa stain assay
• Mechanism Description: The lack of copy number variation of pvgch1 suggests that SP-resistant P. vivax may harbor alternative mechanisms to secure sufficient folate.The quadruple mutant haplotypes 57I/L/58R/61M/117T of pvdhfr gene were the most common (comprising 76% of cases in Myitsone and 43.7% of case in Laiza). The double mutant haplotype 383G/553G of pvdhps gene was also prevalent at each site.

Key Molecule: Hydroxymethylpterin pyrophosphokinase-dihydropteroate synthetase (DHPS) [2]

• Molecule Alteration: SNP; .
• Resistant Disease: Plasmodium vivax malaria [ICD-11: 1F41.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Red blood cells; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: Giemsa stain assay
• Mechanism Description: The lack of copy number variation of pvgch1 suggests that SP-resistant P. vivax may harbor alternative mechanisms to secure sufficient folate.The quadruple mutant haplotypes 57I/L/58R/61M/117T of pvdhfr gene were the most common (comprising 76% of cases in Myitsone and 43.7% of case in Laiza). The double mutant haplotype 383G/553G of pvdhps gene was also prevalent at each site.

ICD-02: Benign/in-situ/malignant neoplasm

Astrocytoma [ICD-11: 2F36]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Missense mutation; p.C59R
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Missense mutation; p.C59R+I164L
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Missense mutation; p.C59R+S108N
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Missense mutation; p.C59R+S108N+I164L
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Missense mutation; p.N51I+C59R
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Missense mutation; p.N51I+C59R+I164L
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Missense mutation; p.N51I+C59R+S108N
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Missense mutation; p.N51I+C59R+S108N+I164L
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Missense mutation; p.A437G
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [3]

• Molecule Alteration: Missense mutation; p.I158V+p.V79I
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [3]

• Molecule Alteration: Missense mutation; p.Y197L
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [3]

• Molecule Alteration: Missense mutation; p.T14A+p.P26Q
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [3]

• Molecule Alteration: Missense mutation; p.M52I+p.E63G+p.T144A+p.K171E
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [3]

• Molecule Alteration: Missense mutation; p.S106P+p.E127G+p.R170G
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

References

• Ref 1: Molecular epidemiology of drug resistance markers of Plasmodium falciparum in Yunnan Province, China. Malar J. 2012 Jul 28;11:243. doi: 10.1186/1475-2875-11-243.
• Ref 2: Polymorphism of Antifolate Drug Resistance in Plasmodium vivax From Local Residents and Migrant Workers Returned From the China-Myanmar Border .Front Cell Infect Microbiol. 2021 Jun 24;11:683423. doi: 10.3389/fcimb.2021.683423. eCollection 2021. 10.3389/fcimb.2021.683423
• Ref 3: Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis. Antimicrob Agents Chemother. 2004 Nov;48(11):4301-5. doi: 10.1128/AAC.48.11.4301-4305.2004.