Drug Information

Drug (ID: DG00041) and It's Reported Resistant Information

• Name: Quinine
• Synonyms: Aflukin; Chinin; Chinine; Chininum; Conchinin; Conquinine; Quindan; Quinidex; Quinidine; Quinimax; Quinina; Quinineanhydrous; Quinora; Quniacridine; Chinin [German]; Kinder Quinina; QUININE MONO HCL; Quinine Dab; Quinine [BAN]; Quinine anhydrous; Quinine bisulfate; Quinine sulfate; Quinine sulphate; Quinoline alkaloid; LT00645788;Q0028; SB01652; Beta-Quinine; Cin-Quin; Coco-Quinine; IBS-L0034250; Kinder Quinina (TN); Legatrin (TN); Quinine (BAN); Quinine, Anhydrous; Quinine, polymers; Quinine, tannate; Biquinate (*Bisulfate heptathydrate*); Dentojel (*Bisulfate heptathydrate*); Quinamm (*2:1 Sulfate salt*), dihydrate; Quine (*2:1 Sulfate salt*, dihydrate); Quinsan (*2:1 Sulfate salt*), dihydrate; Alpha-(6-Methoxy-4-quinoyl)-5-vinyl-2-quinclidinemethanol; Cinchonan-9-ol, 6'-methoxy-, (8.alpha.,9R)-, sulfate; (+)-Quinidine; (-)-Quinine; (1R)-(6-Methoxyquinolin-4-yl)((1S,4S,5R)-5-vinylquinuclidin-2-yl)methanol; (3A,8A,9r)-6'-methoxycinchonan-9-ol; (5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl)-(6-methoxyquinolin-4-yl)methanol; (8-alpha,9R)-6'-Methoxycinchonan-9-ol; (8.alpha.,9R)-6'-Methoxycinchonan-9-ol; (8S,9R)-6'-Methoxycinchonan-9-ol; (8S,9R)-Quinine; (9R)-6'-methoxy-8alpha-cinchonan-9-ol; (R)-(-)-Quinine, 6-methoxycinchonidine; (R)-(-)-quinine; (R)-(6-Methoxy-quinolin-4-yl)-((2S,5S)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methanol; (R)-(6-methoxyquinolin-4-yl)((2S,4S,8R)-8-vinylquinuclidin-2-yl)methanol; (R)-[(2S,4R,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol; (R)-[(2S,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol; (R)-[(2S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol; (S)-(5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl)-(6-methoxyquinolin-4-yl)methanol; (S)-[(2R,4R,5S)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol; 6'-Methoxycinchonan-9-ol; 6'-Methoxycinchonidine; 6'-Methoxycinchonine; 6-Methoxycinchonine
• Indication:
  In total 1 Indication(s)
  Malaria [ICD-11: 1F45]; Approved; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Astrocytoma [ICD-11: 2F36]; [3]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Astrocytoma [ICD-11: 2F36]; [4]
• Formula: C20H24N2O2
• IsoSMILES: COC1=CC2=C(C=CN=C2C=C1)[C@H]([C@@H]3C[C@@H]4CCN3C[C@@H]4C=C)O
• InChI: 1S/C20H24N2O2/c1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18/h3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3/t13-,14-,19-,20+/m0/s1
• InChIKey: LOUPRKONTZGTKE-WZBLMQSHSA-N
• PubChem CID: 3034034
• ChEBI ID: CHEBI:15854
• TTD Drug ID: D03DDR
• VARIDT ID: DR00054
• DrugBank ID: DB00468

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Staphylococcus meningitis [ICD-11: 1B54]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Transmembrane protein 94 (TMEM94) [5]

• Sensitive Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Molecule Alteration: Methylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: S. aureus isolates; 41687
• Experiment for Molecule Alteration: PCR; Docking assay
• Experiment for Drug Resistance: Antimicrobial susceptibility testing; Phenotypic assay; MIC assay; Checkerboard microdilution assay
• Mechanism Description: This study aimed to identify the prevalence of erythromycin and erythromycin-induced resistance and assess for potential inhibitors. A total of 99 isolates were purified from various clinical sources. Phenotypic detection of macrolide-lincosamide-streptogramin B (MLSB)-resistance phenotypes was performed by D-test. MLSB-resistance genes were identified using PCR. Different compounds were tested for their effects on erythromycin and inducible clindamycin resistance by broth microdilution and checkerboard microdilution methods. The obtained data were evaluated using docking analysis. Ninety-one isolates were S. aureus. The prevalence of constitutive MLSB, inducible MLSB, and macrolide-streptogramin (MS) phenotypes was 39.6%, 14.3%, and 2.2%, respectively. Genes including ermC, ermA, ermB, msrA, msrB, lnuA, and mphC were found in 82.6%, 5.8%, 7.7%, 3.8%, 3.8%, 13.5%, and 3.8% of isolates, respectively. Erythromycin resistance was significantly reduced by doxorubicin, neomycin, and omeprazole. Quinine, ketoprofen, and fosfomycin combated and reversed erythromycin/clindamycin-induced resistance. This study highlighted the significance of managing antibiotic resistance and overcoming clindamycin treatment failure. Doxorubicin, neomycin, omeprazole, quinine, ketoprofen, and fosfomycin could be potential inhibitors of erythromycin and inducible clindamycin resistance.

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

Astrocytoma [ICD-11: 2F36]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Chloroquine resistance transporter (CRT) [4], [6]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.76T
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR; Genotypic characterization assay
• Mechanism Description: Pfcrt is involved in the transport of quinine and that SNPs in pfcrt, including 76T, decrease P. falciparum susceptibility to quinine.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [7]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.M908L
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax isolates; 5855
• Experiment for Molecule Alteration: In vitro drug assay
• Experiment for Drug Resistance: Analysis of genetic polymorphisms assay
• Mechanism Description: The pvmdr1 M908L substitutions in pvmdr1 in our samples was associated with reduced sensitivity to chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate and dihydroartem.

Key Molecule: Chloroquine resistance transporter (CRT) [8]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.I356T
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Drug Resistance: Malaria Ag Celisa kit assay
• Mechanism Description: The mutation I356T, identified in 54.7% (n = 326) of the African isolates, was significantly associated with reduced susceptibility to quinine (p < 0.02) and increased susceptibility to mefloquine.

Key Molecule: Chloroquine resistance transporter (CRT) [9]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Phosphorylation of Ser-33 augments the level of PfCRT-conferred resistance to the antimalarial drugs chloroquine and quinine via stimulation of the transport velocity.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.184F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Genotypic characterization assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Eighty-two percent of parasites resistant to quinine carried mutant alleles at these codons (Pfmdr1-86Y, Pfmdr1-184F, and Pfcrt-76T), whereas 74% of parasites susceptible to quinine carried the wild-type allele (Pfmdr1-N86, Pfmdr1-Y184, and Pfcrt-k76, respect.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.86Y
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Genotypic characterization assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Eighty-two percent of parasites resistant to quinine carried mutant alleles at these codons (Pfmdr1-86Y, Pfmdr1-184F, and Pfcrt-76T), whereas 74% of parasites susceptible to quinine carried the wild-type allele (Pfmdr1-N86, Pfmdr1-Y184, and Pfcrt-k76, respect.

Key Molecule: Na+/H+ exchanger-1 (PFNHE1) [4]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation + Chromosome variation; ms4760+ 3 DNNND repeats
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Genotypic characterization assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Eighty-two percent of parasites resistant to quinine carried mutant alleles at these codons (Pfmdr1-86Y, Pfmdr1-184F, and Pfcrt-76T), whereas 74% of parasites susceptible to quinine carried the wild-type allele (Pfmdr1-N86, Pfmdr1-Y184, and Pfcrt-k76, respect.

Key Molecule: Drug/Homo sapiens transporter 1 (DMT1/SLC11A2) [3]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Mutations; Y107N+S129L
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Human red blood cells; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: Human liver-chimeric mouse model; Mus musculus
• Experiment for Molecule Alteration: Genetic cross assay; Bulk segregant analysis; Progeny cloning assay
• Experiment for Drug Resistance: Gene editing
• Mechanism Description: For QN, resistance mapped to a dominant chromosome 7 peak centered 295 kb downstream of pfcrt, with pfcrt showing a smaller peak. We identified the drug/metabolite transporter 1 (DMT1) as the top chromosome 7 candidate due to its structural similarity to PfCRT and proximity to the peak. Deleting DMT1 in QN-resistant Cam3.II parasites significantly sensitized the parasite to QN but not to the other drugs tested, suggesting that DMT1 mediates QN response specifically. We localized DMT1 to structures associated with vesicular trafficking, as well as the parasitophorous vacuolar membrane, lipid bodies, and the digestive vacuole. We also observed that mutant DMT1 transports more QN than the wild-type isoform in vitro. Gene editing confirmed an additional role for mutant PfCRT in mediating QN resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1], [2]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.184F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Genotypic characterization assay
• Experiment for Drug Resistance: [3H]-hypoxanthine assay; In vitro sensitivity assay
• Mechanism Description: 86Y allele exhibited significantly increased QN sensitivity compared with the wild-type counterpart. The parasites with the pfmdr1 184F allele exhibited approximately twice less susceptible to QN than the parasites with the pfmd.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1], [2]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.86Y
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Genotypic characterization assay
• Experiment for Drug Resistance: [3H]-hypoxanthine assay; In vitro sensitivity assay
• Mechanism Description: 86Y allele exhibited significantly increased QN sensitivity compared with the wild-type counterpart. The parasites with the pfmdr1 184F allele exhibited approximately twice less susceptible to QN than the parasites with the pfmd.

Key Molecule: Chloroquine resistance transporter (CRT) [10], [11]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.K76I
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Sequence assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: In addition to producing CQ resistance in P. falciparum, a novel PfCRT k76I mutation resulted in a dramatic increase in QN susceptibility, reversing the normally observed potency order of QD > QN.

Key Molecule: Chloroquine resistance transporter (CRT) [12]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.T93S+p.H97Y+p.F145I+p.I218F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Drug combination assay
• Mechanism Description: The presence of novel pfcrt mutations (T93S, H97Y, F145I, and I218F) with E415G-Exo mutation can confer PPQ-resistance, in the absence of pfpm2 amplification. In vitro testing of PPQ resistant parasites demonstrated a bimodal dose-response, the existence of a swollen digestive vacuole phenotype, and an increased susceptibility to quinine, chloroquine, mefloquine and lumefa.

Key Molecule: Chloroquine resistance transporter (CRT) [9]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.S33A
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Substituting Ser-33 with alanine reduced chloroquine and quinine resistance by 50% compared with the parental P. falciparum strain Dd2, whereas the phosphomimetic amino acid aspartic acid could fully and glutamic acid could partially reconstitute the level of chloroquine/quinine resistance.

Key Molecule: Chloroquine resistance transporter (CRT) [13]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.C101F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum asexual blood-stage parasites; 5833
• Experiment for Molecule Alteration: DNA clones asssay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: This mutation (C101F) also reversed Dd2-mediated CQ resistance, sensitized parasites to amodiaquine, quinine, and artemisinin, and conferred amantadine and blasticidin resistance.

Key Molecule: Chloroquine resistance transporter (CRT) [14]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Mechanism Description: This study describes the activities of a series of dimeric quinine compounds. These agents were found to be the most potent inhibitors of PfCRTCQR described to date with IC50 values between 1 and 5 M but are not themselves substrates of the transporter.

References

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