Molecule Information

General Information of the Molecule (ID: Mol00879)
Name
Chloroquine resistance transporter (CRT) ,Plasmodium falciparum
Synonyms
PfCRT
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Molecule Type
Protein
Gene Name
CRT
Sequence
MKFASKKNNQKNSSKNDERYRELDNLVQEGNGSRLGGGSCLGKCAHVFKLIFKEIKDNIF
IYILSIIYLSVCVMNKIFAKRTLNKIGNYSFVTSETHNFICMIMFFIVYSLFGNKKGNSK
ERHRSFNLQFFAISMLDACSVILAFIGLTRTTGNIQSFVLQLSIPINMFFCFLILRYRYH
LYNYLGAVIIVVTIALVEMKLSFETQEENSIIFNLVLISALIPVCFSNMTREIVFKKYKI
DILRLNAMVSFFQLFTSCLILPVYTLPFLKQLHLPYNEIWTNIKNGFACLFLGRNTVVEN
CGLGMAKLCDDCDGAWKTFALFSFFNICDNLITSYIIDKFSTMTYTIVSCIQGPAIAIAY
YFKFLAGDVVREPRLLDFVTLFGYLFGSIIYRVGNIILERKKMRNEENEDSEGELTNVDS
IITQ
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Function
May regulate endogenous transporter.
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Uniprot ID
CRT_PLAFA
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Kingdom: N.A.
Phylum: Apicomplexa
Class: Aconoidasida
Order: Haemosporida
Family: Plasmodiidae
Genus: Plasmodium
Species: Plasmodium falciparum
Type(s) of Resistant Mechanism of This Molecule
  IDUE: Irregularity in Drug Uptake and Drug Efflux
Drug Resistance Data Categorized by Drug
Approved Drug(s)
9 drug(s) in total
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Amodiaquine
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [1]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Amodiaquine
 Drug Info 
Molecule Alteration Missense mutation
p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 MIP probes and PCR sequencing assay
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description Increasingly, molecular genetic markers for antimalarial drug resistance have been identified, an advance that facilitates the monitoring of the emergence and spread of resistance. Currently, reliable molecular markers are available for P. falciparum resistance to artemisinins (mutations in the propeller region of Pfkelch), sulfadoxine-pyrimethamine (mutations in the dihydrofolate reductase [PfDHFR] and dihydropteroate synthase [PfDHPS] genes), mefloquine (MQ) (amplification of the multidrug resistance-1 gene [PfMDR1]), and piperaquine (amplification of PfPlasmepsin2/3 and specific mutations in the P. falciparum chloroquine resistance transporter gene.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [2]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Amodiaquine
 Drug Info 
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.
Artemisinin
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [2]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Artemisinin
 Drug Info 
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.
Chloroquine
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [3], [4], [5]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.H97Y
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 PacBio amplicon sequencing assay; Whole genome sequencing assay
Experiment for
Drug Resistance		 Piperaquine susceptibility testing assay
Mechanism Description In parasites with single-copy pfpm2, those with the PfCRT F145I, G353V, or I218F mutations had a significantly greater log10-transformed piperaquine IC90 compared to Dd2 (linear regression; P <.0001, P =.0022, and P =.019, respectively), while other mutations did not show a significant difference in piperaquine IC90 compared to Dd2 (perhaps owing to smaller sample.
Disease Class: Malaria [6], [7], [8]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 MIP probes and PCR sequencing assay
Experiment for
Drug Resistance		 SYBR Green I detection assay; [3H]-hypoxanthine assay
Mechanism Description Notably, the PfCRT Lys76Thr substitution was associated with significantly decreased susceptibility to chloroquine, monodesethylamodiaquine, and AQ-13; associations with other aminoquinolines were not conclusive.
Disease Class: Malaria [4], [9], [10]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.C350R
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Amino acid sequence alignments assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Functional studies on the newly emerging PfCRT F145I and C350R mutations, associated with decreased PPQ susceptibility in Asia and South America respectively reveal their ability to mediate PPQ transport in 7G8 variant proteins and to confer resistance in gene-edited parasites. The apparent dichotomy observed between CQ and PPQ for the F145I and C350R mutants, which evolved on CQ-R isoforms and caused CQ resensitization along with a gain of PPQ resistance, highlights the value of extending this research to rapidly emerging PfCRT mutations.
Disease Class: Malaria [11], [12]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.M74I
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Direct DNA sequencing method assay
Mechanism Description High prevalence of mutant Pfcrt genotypes associated with chloroquine resistance in Assam and Arunachal Pradesh, India. The k76T mutation was observed in 77.78% cases followed by M74I (61.11%), N75E (61.11%) and C72S (16.67%). Triple mutant allele M74I+N75E+k76T was found in 61.11% P. falciparum field isolates. Double mutant allele C72S+k76T was seen among 16.67% samples.
Disease Class: Malaria [11], [12]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.N75E
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Direct DNA sequencing method assay
Mechanism Description High prevalence of mutant Pfcrt genotypes associated with chloroquine resistance in Assam and Arunachal Pradesh, India. The k76T mutation was observed in 77.78% cases followed by M74I (61.11%), N75E (61.11%) and C72S (16.67%). Triple mutant allele M74I+N75E+k76T was found in 61.11% P. falciparum field isolates. Double mutant allele C72S+k76T was seen among 16.67% samples.
Disease Class: Malaria [7], [12]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.A220S
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description Plasmodium falciparum chloroquine resistance (CQR) transporter protein (PfCRT) is the important key of CQR. There is a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Almost all of the parasites characterized carried the previously reported mutations k76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at k76A and E198K.
Disease Class: Malaria [7], [12]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.I356T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description Plasmodium falciparum chloroquine resistance (CQR) transporter protein (PfCRT) is the important key of CQR. There is a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Almost all of the parasites characterized carried the previously reported mutations k76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at k76A and E198K.
Disease Class: Malaria [7], [12]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.N326S
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description Plasmodium falciparum chloroquine resistance (CQR) transporter protein (PfCRT) is the important key of CQR. There is a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Almost all of the parasites characterized carried the previously reported mutations k76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at k76A and E198K.
Disease Class: Malaria [7], [12]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.R371I
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description Plasmodium falciparum chloroquine resistance (CQR) transporter protein (PfCRT) is the important key of CQR. There is a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Almost all of the parasites characterized carried the previously reported mutations k76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at k76A and E198K.
Disease Class: Malaria [13]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.C101F+p.F145I+p.M343L+p.G353V+T93S+I218F
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum D10 5833
Plasmodium falciparum Dd2 5833
Plasmodium falciparum PfCRT 5833
Experiment for
Molecule Alteration		 Western blotting analysis
Mechanism Description Plasmodium falciparum parasites resistant to chloroquine, amodiaquine, or piperaquine harbor mutations in the P. falciparum chloroquine resistance transporter (PfCRT), a transporter resident on the digestive vacuole membrane that in its variant forms can transport these weak-base 4-aminoquinoline drugs out of this acidic organelle, thus preventing these drugs from binding heme and inhibiting its detoxification.
Disease Class: Malaria [14]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.C101
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum isolate 3D7 5833
Plasmodium falciparum isolate 7G8 5833
Plasmodium falciparum isolate Dd2 5833
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 P. falciparum proliferation assay
Mechanism Description Drug-resistance-conferring mutations reduce both the peptide transport capacity and substrate range of PfCRT, explaining the impaired fitness of drug-resistant parasites. Two PfCRT mutations that arose separately under in vitro drug pressure (C101F and L272F) incur both a fitness cost and a monstrously swollen DV. Three laboratory-derived isoforms that cause a gross enlargement of the DV-L272F-PfCRT3D7, L272F-PfCRTDd2 and C101F-PfCRTDd2-displayed unusually low capacities for VF-6 tra.
Disease Class: Malaria [14]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.L272F
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum isolate 3D7 5833
Plasmodium falciparum isolate 7G8 5833
Plasmodium falciparum isolate Dd2 5833
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 P. falciparum proliferation assay
Mechanism Description Drug-resistance-conferring mutations reduce both the peptide transport capacity and substrate range of PfCRT, explaining the impaired fitness of drug-resistant parasites. Two PfCRT mutations that arose separately under in vitro drug pressure (C101F and L272F) incur both a fitness cost and a monstrously swollen DV. Three laboratory-derived isoforms that cause a gross enlargement of the DV-L272F-PfCRT3D7, L272F-PfCRTDd2 and C101F-PfCRTDd2-displayed unusually low capacities for VF-6 tra.
Disease Class: Malaria [4]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.C101F
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum W2 5833
Experiment for
Molecule Alteration		 Pfcrt genotyping assay
Experiment for
Drug Resistance		 HRP2 ELISA-based assay Malaria Ag Celisa kit assay
Mechanism Description In a context of dihydroartemisinin-piperaquine resistance in Cambodia and high prevalence of k13 C580Y mutation associated with artemisinin resistance, new pfcrt mutations (H97Y, M343L, and G353V) were revealed to induce in vitro piperaquine resistance. Treatment failures with dihydroartemisinin-piperaquine were associated with T93S, H97Y, F145I and I218F mutations in PfCRT and with plasmepsin 2/3 amplification in Cambodia, Thailand and Vietnam.
Disease Class: Malaria [4]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.F145I
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum W2 5833
Experiment for
Molecule Alteration		 Pfcrt genotyping assay
Experiment for
Drug Resistance		 HRP2 ELISA-based assay Malaria Ag Celisa kit assay
Mechanism Description In a context of dihydroartemisinin-piperaquine resistance in Cambodia and high prevalence of k13 C580Y mutation associated with artemisinin resistance, new pfcrt mutations (H97Y, M343L, and G353V) were revealed to induce in vitro piperaquine resistance. Treatment failures with dihydroartemisinin-piperaquine were associated with T93S, H97Y, F145I and I218F mutations in PfCRT and with plasmepsin 2/3 amplification in Cambodia, Thailand and Vietnam.
Disease Class: Malaria [4]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.G353V
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum W2 5833
Experiment for
Molecule Alteration		 Pfcrt genotyping assay
Experiment for
Drug Resistance		 HRP2 ELISA-based assay Malaria Ag Celisa kit assay
Mechanism Description In a context of dihydroartemisinin-piperaquine resistance in Cambodia and high prevalence of k13 C580Y mutation associated with artemisinin resistance, new pfcrt mutations (H97Y, M343L, and G353V) were revealed to induce in vitro piperaquine resistance. Treatment failures with dihydroartemisinin-piperaquine were associated with T93S, H97Y, F145I and I218F mutations in PfCRT and with plasmepsin 2/3 amplification in Cambodia, Thailand and Vietnam.
Disease Class: Malaria [4]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.M343L
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum W2 5833
Experiment for
Molecule Alteration		 Pfcrt genotyping assay
Experiment for
Drug Resistance		 HRP2 ELISA-based assay Malaria Ag Celisa kit assay
Mechanism Description In a context of dihydroartemisinin-piperaquine resistance in Cambodia and high prevalence of k13 C580Y mutation associated with artemisinin resistance, new pfcrt mutations (H97Y, M343L, and G353V) were revealed to induce in vitro piperaquine resistance. Treatment failures with dihydroartemisinin-piperaquine were associated with T93S, H97Y, F145I and I218F mutations in PfCRT and with plasmepsin 2/3 amplification in Cambodia, Thailand and Vietnam.
Disease Class: Malaria [4]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.T93S
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum W2 5833
Experiment for
Molecule Alteration		 Pfcrt genotyping assay
Experiment for
Drug Resistance		 HRP2 ELISA-based assay Malaria Ag Celisa kit assay
Mechanism Description In a context of dihydroartemisinin-piperaquine resistance in Cambodia and high prevalence of k13 C580Y mutation associated with artemisinin resistance, new pfcrt mutations (H97Y, M343L, and G353V) were revealed to induce in vitro piperaquine resistance. Treatment failures with dihydroartemisinin-piperaquine were associated with T93S, H97Y, F145I and I218F mutations in PfCRT and with plasmepsin 2/3 amplification in Cambodia, Thailand and Vietnam.
Disease Class: Malaria [12]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.C72S
Experimental Note Discovered Using In-vivo Testing Model
Mechanism Description Mutant PfCRT molecules have acquired the ability to expel CQ out of the DV. All CQR haplotypes carry the key k76T mutation that removes a positive charge in TM 1, suggesting a charge-dependent transport mechanism as CQ is di-protonated in the acidic DV10,13. The k76T mutation is always accompanied by additional mutations which may increase the CQR level and/or attenuate the fitness cost of resistance.
Disease Class: Malaria [12]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.I356L
Experimental Note Discovered Using In-vivo Testing Model
Mechanism Description Mutant PfCRT molecules have acquired the ability to expel CQ out of the DV. All CQR haplotypes carry the key k76T mutation that removes a positive charge in TM 1, suggesting a charge-dependent transport mechanism as CQ is di-protonated in the acidic DV10,13. The k76T mutation is always accompanied by additional mutations which may increase the CQR level and/or attenuate the fitness cost of resistance.
Disease Class: Malaria [12]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.N326D
Experimental Note Discovered Using In-vivo Testing Model
Mechanism Description Mutant PfCRT molecules have acquired the ability to expel CQ out of the DV. All CQR haplotypes carry the key k76T mutation that removes a positive charge in TM 1, suggesting a charge-dependent transport mechanism as CQ is di-protonated in the acidic DV10,13. The k76T mutation is always accompanied by additional mutations which may increase the CQR level and/or attenuate the fitness cost of resistance.
Disease Class: Malaria [9]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.F145I;
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Amino acid sequence alignments assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Functional studies on the newly emerging PfCRT F145I and C350R mutations, associated with decreased PPQ susceptibility in Asia and South America respectively reveal their ability to mediate PPQ transport in 7G8 variant proteins and to confer resistance in gene-edited parasites. The apparent dichotomy observed between CQ and PPQ for the F145I and C350R mutants, which evolved on CQ-R isoforms and caused CQ resensitization along with a gain of PPQ resistance, highlights the value of extending this research to rapidly emerging PfCRT mutations.
Disease Class: Malaria [15]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
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 blotting analysis
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description Phosphorylation at Ser-33 and Ser-411 of PfCRT of the chloroquine-resistant P. falciparum strain Dd2 and kinase inhibitors can sensitize drug responsiveness.
Disease Class: Malaria [11]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.C72S
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Direct DNA sequencing method assay
Mechanism Description High prevalence of mutant Pfcrt genotypes associated with chloroquine resistance in Assam and Arunachal Pradesh, India. The k76T mutation was observed in 77.78% cases followed by M74I (61.11%), N75E (61.11%) and C72S (16.67%). Triple mutant allele M74I+N75E+k76T was found in 61.11% P. falciparum field isolates. Double mutant allele C72S+k76T was seen among 16.67% samples.
Disease Class: Malaria [11]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.C72S+p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Direct DNA sequencing method assay
Mechanism Description High prevalence of mutant Pfcrt genotypes associated with chloroquine resistance in Assam and Arunachal Pradesh, India. The k76T mutation was observed in 77.78% cases followed by M74I (61.11%), N75E (61.11%) and C72S (16.67%). Triple mutant allele M74I+N75E+k76T was found in 61.11% P. falciparum field isolates. Double mutant allele C72S+k76T was seen among 16.67% samples.
Disease Class: Malaria [11]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.M74I+p.N75E+p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Direct DNA sequencing method assay
Mechanism Description High prevalence of mutant Pfcrt genotypes associated with chloroquine resistance in Assam and Arunachal Pradesh, India. The k76T mutation was observed in 77.78% cases followed by M74I (61.11%), N75E (61.11%) and C72S (16.67%). Triple mutant allele M74I+N75E+k76T was found in 61.11% P. falciparum field isolates. Double mutant allele C72S+k76T was seen among 16.67% samples.
Disease Class: Malaria [16]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Chromosome variation
Dd2 genotype
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Drug Resistance		 lactate dehydrogenase (pLDH) assay
Mechanism Description Chloroquine resistance-conferring isoforms of PfCRT reduced the susceptibility of the parasite to QC, MB, and AO. In chloroquine-resistant (but not chloroquine-sensitive) parasites, AO and QC increased the parasite's accumulation of, and susceptibility to, chloroquine. All 3 compounds were shown to bind to Pf.
Disease Class: Malaria [16]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Chromosome variation
K1 genotype
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Drug Resistance		 lactate dehydrogenase (pLDH) assay
Mechanism Description Chloroquine resistance-conferring isoforms of PfCRT reduced the susceptibility of the parasite to QC, MB, and AO. In chloroquine-resistant (but not chloroquine-sensitive) parasites, AO and QC increased the parasite's accumulation of, and susceptibility to, chloroquine. All 3 compounds were shown to bind to Pf.
Disease Class: Malaria [17]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
Mutant pfcrt alleles PH1 and PH2
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced.
Disease Class: Malaria [8]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum C-1Dd2 5833
Plasmodium falciparum C2GC03 5833
Plasmodium falciparum C3Dd2 5833
Plasmodium falciparum C67G8 5833
Plasmodium falciparum GC03 5833
Plasmodium falciparum T76k-1Dd2 5833
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description The k76T mutation in PfCRT generates structural changes that are sufficient to allow GSH transport, but not CQ transport. mutant pfcrt allows enhanced transport of GSH into the parasite's DV. The elevated levels of GSH in the DV reduce the level of free heme available for CQ binding, which mediates the lower susceptibility to CQ in the PfCRT mutant parasites.
Disease Class: Malaria [18]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.H97L
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Nested PCR
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description Parasites with a chloroquine IC50 > 100 nM were significantly associated with PfCRT 97L and pfmdr1 184F, and a pfmdr1 copy number >= 4 was more common in those with a chloroquine IC50 <=100 nM.
Disease Class: Malaria [7]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.E198K
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description Plasmodium falciparum chloroquine resistance (CQR) transporter protein (PfCRT) is the important key of CQR. There is a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Almost all of the parasites characterized carried the previously reported mutations k76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at k76A and E198K.
Disease Class: Malaria [7]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.K76A
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description Plasmodium falciparum chloroquine resistance (CQR) transporter protein (PfCRT) is the important key of CQR. There is a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Almost all of the parasites characterized carried the previously reported mutations k76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at k76A and E198K.
Disease Class: Malaria [7]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.Q271E
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description Plasmodium falciparum chloroquine resistance (CQR) transporter protein (PfCRT) is the important key of CQR. There is a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Almost all of the parasites characterized carried the previously reported mutations k76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at k76A and E198K.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [19], [20], [21]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Chloroquine
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 SYBR Green I detection assay; [3H]-hypoxanthine assay
Mechanism Description Phosphorylation at Ser-33 and Ser-411 of PfCRT of the chloroquine-resistant P. falciparum strain Dd2 and kinase inhibitors can sensitize drug responsiveness.
Disease Class: Malaria [2]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Chloroquine
 Drug Info 
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.
Disease Class: Fungal infection [22]
Sensitive Disease Fungal infection [ICD-11: 1F29-1F2F]
 Disease Info 
Sensitive Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.A144T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Saccharomyces cerevisiae BY4741 (MATa his3deta1 leu2deta met15deta ura3deta) 1247190
Saccharomyces cerevisiae CH1305 (MAT a ade2 ade3 ura3 - 52 leu2 lys2 - 801 ) 4932
Saccharomyces cerevisiae detaVma (MATa leu2deta met15deta ura3deta) 4932
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Colony formation assay
Mechanism Description The sequences of PfCRT isoforms 'PH1' and 'PH2', which harbour novel mutations A144T and L160Y. Two isoforms (PH1 and PH2 PfCRT) were found to be intrinsically toxic to yeast, even in the absence.
Disease Class: Fungal infection [22]
Sensitive Disease Fungal infection [ICD-11: 1F29-1F2F]
 Disease Info 
Sensitive Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.L160Y
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Saccharomyces cerevisiae BY4741 (MATa his3deta1 leu2deta met15deta ura3deta) 1247190
Saccharomyces cerevisiae CH1305 (MAT a ade2 ade3 ura3 - 52 leu2 lys2 - 801 ) 4932
Saccharomyces cerevisiae detaVma (MATa leu2deta met15deta ura3deta) 4932
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Colony formation assay
Mechanism Description The sequences of PfCRT isoforms 'PH1' and 'PH2', which harbour novel mutations A144T and L160Y. Two isoforms (PH1 and PH2 PfCRT) were found to be intrinsically toxic to yeast, even in the absence.
Disease Class: Malaria [23]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.C101F
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum 3D7 36329
Plasmodium falciparum 3D7L272F mutant 36329
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description Carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82% when expressed in Xenopus oocytes.
Disease Class: Malaria [23]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.L272F
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum 3D7 36329
Plasmodium falciparum 3D7L272F mutant 36329
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description Carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82% when expressed in Xenopus oocytes.
Disease Class: Malaria [20]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.S163R
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Plasmodium falciparum D10 5833
Plasmodium falciparum Dd2 5833
Plasmodium falciparum PfCRT 5833
Mechanism Description T76k and S163R mutations in PfCRTCQR restore CQ sensitivity to CQR parasites. The introduction of either one of these changes to PfCRTCQR, each of which entailed the addition of a positive charge to the putative substrate-binding site of the protein, resulted in the loss of CQ transport activity.
Disease Class: Malaria [20]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Chloroquine
 Drug Info 
Molecule Alteration Missense mutation
p.T76K
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Plasmodium falciparum D10 5833
Plasmodium falciparum Dd2 5833
Plasmodium falciparum PfCRT 5833
Mechanism Description T76k and S163R mutations in PfCRTCQR restore CQ sensitivity to CQR parasites. The introduction of either one of these changes to PfCRTCQR, each of which entailed the addition of a positive charge to the putative substrate-binding site of the protein, resulted in the loss of CQ transport activity.
Chlorpheniramine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [24]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chlorpheniramine
 Drug Info 
Molecule Alteration Missense mutation
p.K76N
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum 5833
Experiment for
Drug Resistance		 Malaria SYBR Green I-based fluorescence (MSF) method assay
Mechanism Description Mutations within PfCRT, particularly changes from a charged amino acid residue (lysine, k76) to an uncharged residue (such as threonine [76T], asparagine [76N], or isoleucine [76I]), seem to be important not only in the acquisition of resistance to quinoline antimalarials (e.g., by allowing efflux of diprotic CQ), but also in the mechanism of resistance reversal actions for chemosens.
Disease Class: Malaria [24]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Chlorpheniramine
 Drug Info 
Molecule Alteration Missense mutation
p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum 5833
Experiment for
Drug Resistance		 Malaria SYBR Green I-based fluorescence (MSF) method assay
Mechanism Description Mutations within PfCRT, particularly changes from a charged amino acid residue (lysine, k76) to an uncharged residue (such as threonine [76T], asparagine [76N], or isoleucine [76I]), seem to be important not only in the acquisition of resistance to quinoline antimalarials (e.g., by allowing efflux of diprotic CQ), but also in the mechanism of resistance reversal actions for chemosens.
Glutathione
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [8]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Glutathione
 Drug Info 
Molecule Alteration Missense mutation
p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum C-1Dd2 5833
Plasmodium falciparum C2GC03 5833
Plasmodium falciparum C3Dd2 5833
Plasmodium falciparum C67G8 5833
Plasmodium falciparum GC03 5833
Plasmodium falciparum T76k-1Dd2 5833
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description The k76T mutation in PfCRT generates structural changes that are sufficient to allow GSH transport, but not CQ transport. mutant pfcrt allows enhanced transport of GSH into the parasite's DV. The elevated levels of GSH in the DV reduce the level of free heme available for CQ binding, which mediates the lower susceptibility to CQ in the PfCRT mutant parasites.
Mefloquine
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [1]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Mefloquine
 Drug Info 
Molecule Alteration Missense mutation
p.N86Y
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 MIP probes and PCR sequencing assay
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description Despite the availability of few mutant parasites for comparison, the PfMDR1 Asn86Tyr substitution appeared to be associated with increased susceptibility to lumefantrine and mefloquine, as seen prev.
Disease Class: Malaria [25]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Mefloquine
 Drug Info 
Molecule Alteration Missense mutation
p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Nested PCR
Mechanism Description Both in vitro and molecular surveillance studies have associated CQ resistance mainly with the pfcrt 76T allele, but also with pfmdr1 86Y and 184F alleles. Pfcrt 76T and pfmdr1 86Y mutant alleles have also been reported to decrease P. falciparum susceptibility to amodiaquine but increase parasite sensitivity to dihydroartemisinin, lumefantrine and mefl.
Piperaquine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [3], [4], [5]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Piperaquine
 Drug Info 
Molecule Alteration Missense mutation
p.H97Y
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 MIP probes and PCR sequencing assay
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description In contrast, gene-edited parasites with PfCRT H97Y, F145I, M343L, or G353V mutations are resistant to piperaquine in vitro.
Disease Class: Malaria [3], [1]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Piperaquine
 Drug Info 
Molecule Alteration Missense mutation
p.F145I
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 MIP probes and PCR sequencing assay
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description In contrast, gene-edited parasites with PfCRT H97Y, F145I, M343L, or G353V mutations are resistant to piperaquine in vitro.
Disease Class: Malaria [3], [1]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Piperaquine
 Drug Info 
Molecule Alteration Missense mutation
p.G353V
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 MIP probes and PCR sequencing assay
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description In contrast, gene-edited parasites with PfCRT H97Y, F145I, M343L, or G353V mutations are resistant to piperaquine in vitro.
Disease Class: Malaria [3], [1]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Piperaquine
 Drug Info 
Molecule Alteration Missense mutation
p.M343L
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 MIP probes and PCR sequencing assay
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description In contrast, gene-edited parasites with PfCRT H97Y, F145I, M343L, or G353V mutations are resistant to piperaquine in vitro.
Disease Class: Malaria [5]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Piperaquine
 Drug Info 
Molecule Alteration Missense mutation
p.F145I + p.G353V+ p.I218F
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 PacBio amplicon sequencing assay; Whole genome sequencing assay
Experiment for
Drug Resistance		 Piperaquine susceptibility testing assay
Mechanism Description In parasites with single-copy pfpm2, those with the PfCRT F145I, G353V, or I218F mutations had a significantly greater log10-transformed piperaquine IC90 compared to Dd2 (linear regression; P <.0001, P =.0022, and P =.019, respectively), while other mutations did not show a significant difference in piperaquine IC90 compared to Dd2 (perhaps owing to smaller sample.
Disease Class: Malaria [5]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Piperaquine
 Drug Info 
Molecule Alteration Missense mutation + Chromosome variation
PfCRT p.F145I+p.G353V+p.I218F + Haplotype
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 PacBio amplicon sequencing assay; Whole genome sequencing assay
Experiment for
Drug Resistance		 Piperaquine susceptibility testing assay
Mechanism Description Parasites with the Dd2 haplotype and pfpm2 amplification had significantly greater mean log10-transformed piperaquine IC90 compared to Dd2 parasites without pfpm2 amplification (t test, P =.0079). In parasites with newly emerged PfCRT mutations, mean log10-transformed piperaquine IC90 was not significantly different between parasites with or without pfpm2 amplification.
Disease Class: Malaria [26]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Piperaquine
 Drug Info 
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 blotting analysis
Experiment for
Drug Resistance		 Piperaquine survival assay
Mechanism Description The characterization of culture-adapted isolates revealed that 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.
Disease Class: Malaria [2]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Piperaquine
 Drug Info 
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 Addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC90) or 50% parasite killing.
Pyronaridine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [27]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Pyronaridine
 Drug Info 
Molecule Alteration Missense mutation
p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Drug Resistance		 [3H]-hypoxanthine assay
Mechanism Description The pyronaridine IC50 (inhibitory concentration 50 %) ranged from 0.55 to 80.0 nM. Ex vivo responses to pyronaridine were significantly associated with the k76T mutation (p-value = 0.020). The reduced susceptibility to pyronaridine, defined as IC50 > 60 nM, was significantly associated with the k76T mutation (p-value = 0.004).
Quinine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [28], [29]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Quinine
 Drug Info 
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.
Disease Class: Malaria [4]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Quinine
 Drug Info 
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.
Disease Class: Malaria [15]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Quinine
 Drug Info 
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 blotting 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.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [30], [31]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Quinine
 Drug Info 
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.
Disease Class: Malaria [26]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Quinine
 Drug Info 
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 blotting 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.
Disease Class: Malaria [15]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Quinine
 Drug Info 
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 blotting 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.
Disease Class: Malaria [2]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Quinine
 Drug Info 
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.
Disease Class: Malaria [32]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Quinine
 Drug Info 
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.
Clinical Trial Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
AQ-13
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [33]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug AQ-13
 Drug Info 
Molecule Alteration Missense mutation
p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 MIP probes and PCR sequencing assay
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description Notably, the PfCRT Lys76Thr substitution was associated with significantly decreased susceptibility to chloroquine, monodesethylamodiaquine, and AQ-13; associations with other aminoquinolines were not conclusive.
Lumefantrine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [34]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Lumefantrine
 Drug Info 
Molecule Alteration Missense mutation
p.N326S+p.I356T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Quantitative trait loci (QTL) assay
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description Comparisons of the MEF and HLF responses showed that the Cambodian 803 line, as for LUM, was less susceptible than Ghanaian GB4 to these drugs: the geometric mean EC50s of 803 relative to GB4 were 2.9-fold greater with MEF and 4.6-fold greater with HLF, whereas these were 2.0-fold greater with CQ and 1.7-fold reduced w.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [25]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Lumefantrine
 Drug Info 
Molecule Alteration Missense mutation
p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Nested PCR
Mechanism Description Both in vitro and molecular surveillance studies have associated CQ resistance mainly with the pfcrt 76T allele, but also with pfmdr1 86Y and 184F alleles. Pfcrt 76T and pfmdr1 86Y mutant alleles have also been reported to decrease P. falciparum susceptibility to amodiaquine but increase parasite sensitivity to dihydroartemisinin, lumefantrine and mefl.
Investigative Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
Desethylamodiaquine
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [33]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Desethylamodiaquine
 Drug Info 
Molecule Alteration Missense mutation
p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 MIP probes and PCR sequencing assay
Experiment for
Drug Resistance		 SYBR Green I detection assay
Mechanism Description Notably, the PfCRT Lys76Thr substitution was associated with significantly decreased susceptibility to chloroquine, monodesethylamodiaquine, and AQ-13; associations with other aminoquinolines were not conclusive.
Dihydroartemisinin
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [35]
Resistant Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Resistant Drug Dihydroartemisinin
 Drug Info 
Molecule Alteration Missense mutation
p.F145I
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Mechanism Description The PfCRT 145I mutation was only observed in parasites with amplified plasmepsin II/III copy number, suggesting that perhaps in nature this mutation has only occurred or only attains high frequency on a background of amplified plasmepsin II/III. Moreover, the mean piperaquine IC90 was greater in parasites with both amplified plasmepsin II/III and PfCRT 145I compared with parasites with just amplified plasmepsin II/III, suggesting that 145I results in an additional resistance effect beyond that caused by amplified plasmepsin.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Disease Class: Malaria [25]
Sensitive Disease Malaria [ICD-11: 1F45.0]
 Disease Info 
Sensitive Drug Dihydroartemisinin
 Drug Info 
Molecule Alteration Missense mutation
p.K76T
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Plasmodium falciparum strains 5833
Experiment for
Molecule Alteration		 Nested PCR
Mechanism Description Both in vitro and molecular surveillance studies have associated CQ resistance mainly with the pfcrt 76T allele, but also with pfmdr1 86Y and 184F alleles. Pfcrt 76T and pfmdr1 86Y mutant alleles have also been reported to decrease P. falciparum susceptibility to amodiaquine but increase parasite sensitivity to dihydroartemisinin, lumefantrine and mefl.
References
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