Molecule Information

General Information of the Molecule (ID: Mol01012)

• Name: Multidrug resistance protein 1 (ABCB1) ,Plasmodium falciparum
• Synonyms: Chloroquine resistance protein
• Molecule Type: Protein
• Gene Name: MDR1
• Sequence:
  MGKEQKEKKDGNLSIKEEVEKELNKKSTAELFRKIKNEKISFFLPFKCLPAQHRKLLFIS
  FVCAVLSGGTLPFFISVFGVILKNMNLGDDINPIILSLVSIGLVQFILSMISSYCMDVIT
  SKILKTLKLEYLRSVFYQDGQFHDNNPGSKLRSDLDFYLEQVSSGIGTKFITIFTYASSF
  LGLYIWSLIKNARLTLCITCVFPLIYVCGVICNKKVKLNKKTSLLYNNNTMSIIEEALMG
  IRTVASYCGEKTILNKFNLSETFYSKYILKANFVEALHIGLINGLILVSYAFGFWYGTRI
  IINSATNQYPNNDFNGASVISILLGVLISMFMLTIILPNITEYMKALEATNSLYEIINRK
  PLVENNDDGETLPNIKKIEFKNVRFHYDTRKDVEIYKDLSFTLKEGKTYAFVGESGCGKS
  TILKLIERLYDPTEGDIIVNDSHNLKDINLKWWRSKIGVVSQDPLLFSNSIKNNIKYSLY
  SLKDLEAMENYYEENTNDTYENKNFSLISNSMTSNELLEMKKEYQTIKDSDVVDVSKKVL
  IHDFVSSLPDKYDTLVGSNASKLSGGQKQRISIARAIMRNPKILILDEATSSLDNKSEYL
  VQKTINNLKGNENRITIIIAHRLSTIRYANTIFVLSNRERSDNNNNNNNDDNNNNNNNNN
  NKINNEGSYIIEQGTHDSLMKNKNGIYHLMINNQKISSNKSSNNGNDNGSDNKSSAYKDS
  DTGNDADNMNSLSIHENENISNNRNCKNTAENEKEEKVPFFKRMFRRKKKAPNNLRIIYK
  EIFSYKKDVTIIFFSILVAGGLYPVFALLYARYVSTLFDFANLEYNSNKYSIYILLIAIA
  MFISETLKNYYNNKIGEKVEKTMKRRLFENILYQEMSFFDQDKNTPGVLSAHINRDVHLL
  KTGLVNNIVIFSHFIMLFLVSMVMSFYFCPIVAAVLTFIYFINMRVFAVRARLTKSKEIE
  KKENMSSGVFAFSSDDEMFKDPSFLIQEAFYNMHTVINYGLEDYFCNLIEKAIDYKNKGQ
  KRRIIVNAALWGFSQSAQLFINSFAYWFGSFLIKRGTILVDDFMKSLFTFIFTGSYAGKL
  MSLKGDSENAKLSFEKYYPLMIRKSNIDVRDDGGIRINKNLIKGKVDIKDVNFRYISRPN
  VPIYKNLSFTCDSKKTTAIVGETGSGKSTFMNLLLRFYDLKNDHIILKNDMTNFQDYQNN
  NNNSLVLKNVNEFSNQSGSAEDYTVFNNNGEILLDDINICDYNLRDLRNLFSIVSQEPML
  FNMSIYENIKFGREDATLEDVKRVSKFAAIDEFIESLPNKYDTNVGPYGKSLSGGQKQRI
  AIARALLREPKILLLDEATSSLDSNSEKLIEKTIVDIKDKADKTIITIAHRIASIKRSDK
  IVVFNNPDRNGTFVQSHGTHDELLSAQDGIYKKYVKLAK
• Function: Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
• Uniprot ID: MDR_PLAFF

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) 5 drug(s) in total

Amodiaquine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Amodiaquine
• 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: 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.

Chloroquine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [1], [2], [3]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Chloroquine
• 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: 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.

Disease Class: Malaria [4], [5], [6]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Chloroquine
• Molecule Alteration: Missense mutation; p.Y184F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Nested PCR; Sequence assay
• 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 [2]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Chloroquine
• Molecule Alteration: Missense mutation; p.N86F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Mechanism Description: Resistance to chloroquine (CQ) in P. falciparum parasites is predominantly linked to a single mutation in the P. falciparum transporter gene (Pfcrt) on chromosome 7, which encodes a protein localized on the parasite digestive vacuole (DV) membrane. The replacement of lysine (k) at position 76 to a threonine (T), i.e. the k76T mutation, has been established as the most important prognostic marker of treatment failure. Another point mutation N86Y in P. falciparum multidrug resistance gene 1 (Pfmdr1), on chromosome 5, that encodes a P-glycoprotein homologue and is located on the parasite DV membrane has also been implicated in CQ resistance.

Halofantrine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [7]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Sensitive Drug: Halofantrine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: The presence of non-toxic concentrations of Mk571 sensitized both chloroquine-sensitive and -resistant parasites to mefloquine and halofantrine, likely by competing against PfMDR1-mediated sequestering of the drugs into the DV compartment and away from the drugs' cytosolic targets.

Mefloquine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [8], [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Mefloquine
• Molecule Alteration: Expression; 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: 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)

Disease Class: Malaria [9]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Sensitive Drug: Mefloquine
• Molecule Alteration: Missense mutation; p.N86+p.Y184
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum isolates; 5833
• Experiment for Molecule Alteration: Quantitative trait loci (QTL) assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: By QTL analysis, lumefantrine and mefloquine phenotypes mapped to a chromosome 5 region containing codon polymorphisms N86Y and Y184F in the P. falciparum multidrug resistance 1 protein.

Disease Class: Malaria [3]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Sensitive Drug: Mefloquine
• Molecule Alteration: Missense mutation; p.Y184F
• 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.

Quinine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [10]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Quinine
• 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.

Disease Class: Malaria [10]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Quinine
• 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.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [11], [12]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Sensitive Drug: Quinine
• 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.

Disease Class: Malaria [11], [12]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Sensitive Drug: Quinine
• 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.

Clinical Trial Drug(s) 1 drug(s) in total

Lumefantrine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [8]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Lumefantrine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Drug Resistance: HRP-2 ELISA assay
• Mechanism Description: Isolates with multiple pfmdr1 copies had significantly higher IC50s against OZ78, OZ277, MQ, and LUM. In contrast, no significant differences in IC50s between isolates with single and multiple pfmdr1 copy numbers were observed for the other test compounds.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [1]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Sensitive Drug: Lumefantrine
• 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 [9]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Sensitive Drug: Lumefantrine
• Molecule Alteration: Missense mutation; p.N86+p.Y184
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum isolates; 5833
• Experiment for Molecule Alteration: Quantitative trait loci (QTL) assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: The geometric mean LUM EC50 of 803 was 5.8-fold greater than GB4 (3.21 nM, 95% Confidence Interval 2.80-3.66 nM vs. 0.55 nM, 95% CI 0.46-0.67 nM, respectively). 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 with DHA.

Disease Class: Malaria [3]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Sensitive Drug: Lumefantrine
• 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: 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) 1 drug(s) in total

Dihydroartemisinin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [3]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Sensitive Drug: Dihydroartemisinin
• 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: 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.

Disease Class: Malaria [13]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Sensitive Drug: Dihydroartemisinin
• 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: DNA assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: The most striking phenotype observed with the replacement of N86Y with the wild-type N86 residue was a significant increase in the IC50 and IC90 values for LMF, MFQ and DHA. In the case of DHA, the change to N86 resulted in -1.5-fold increased IC50 values in both backgrounds.

References

• Ref 1: Evolution of Multidrug Resistance in Plasmodium falciparum: a Longitudinal Study of Genetic Resistance Markers in the Greater Mekong Subregion. Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0112121. doi: 10.1128/AAC.01121-21. Epub 2021 Sep 13.
• Ref 2: En-route to the 'elimination' of genotypic chloroquine resistance in Western and Southern Zambia, 14 years after chloroquine withdrawal. Malar J. 2019 Dec 3;18(1):391. doi: 10.1186/s12936-019-3031-4.
• Ref 3: Prevalence of chloroquine and antifolate drug resistance alleles in Plasmodium falciparum clinical isolates from three areas in Ghana. AAS Open Res. 2018 Dec 3;1:1. doi: 10.12688/aasopenres.12825.2. eCollection 2018.
• Ref 4: Role of Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes on in vitro chloroquine resistance in isolates of Plasmodium falciparum from Thailand. Am J Trop Med Hyg. 2011 Oct;85(4):606-11. doi: 10.4269/ajtmh.2011.11-0108.
• Ref 5: Survey of Plasmodium falciparum multidrug resistance-1 and chloroquine resistance transporter alleles in Haiti. Malar J. 2013 Nov 19;12:426. doi: 10.1186/1475-2875-12-426.
• Ref 6: Sequence analysis of pfcrt and pfmdr1 genes and its association with chloroquine resistance in Southeast Indian Plasmodium falciparum isolates. Genom Data. 2016 Apr 18;8:85-90. doi: 10.1016/j.gdata.2016.04.010. eCollection 2016 Jun.
• Ref 7: A 2-amino quinoline, 5-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoic acid, interacts with PfMDR1 and inhibits its drug transport in Plasmodium falciparum. Mol Biochem Parasitol. 2014 Jun;195(1):34-42. doi: 10.1016/j.molbiopara.2014.05.006. Epub 2014 Jun 8.
• Ref 8: Ex vivo activity of endoperoxide antimalarials, including artemisone and arterolane, against multidrug-resistant Plasmodium falciparum isolates from Cambodia. Antimicrob Agents Chemother. 2014 Oct;58(10):5831-40. doi: 10.1128/AAC.02462-14. Epub 2014 Jul 21.
• Ref 9: Evidence for linkage of pfmdr1, pfcrt, and pfk13 polymorphisms to lumefantrine and mefloquine susceptibilities in a Plasmodium falciparum cross. Int J Parasitol Drugs Drug Resist. 2020 Dec;14:208-217. doi: 10.1016/j.ijpddr.2020.10.009. Epub 2020 Oct 27.
• Ref 10: Polymorphisms in Pfmdr1, Pfcrt, and Pfnhe1 genes are associated with reduced in vitro activities of quinine in Plasmodium falciparum isolates from western Kenya. Antimicrob Agents Chemother. 2014 Jul;58(7):3737-43. doi: 10.1128/AAC.02472-14. Epub 2014 Apr 21.
• Ref 11: Distribution of pfmdr1 polymorphisms in Plasmodium falciparum isolated from Southern Thailand. Malar J. 2014 Mar 27;13:117. doi: 10.1186/1475-2875-13-117.
• Ref 12: Phenotypic and genotypic characterization of Thai isolates of Plasmodium falciparum after an artemisinin resistance containment project. Malar J. 2018 May 15;17(1):197. doi: 10.1186/s12936-018-2347-9.
• Ref 13: Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies. Nat Commun. 2016 May 18;7:11553. doi: 10.1038/ncomms11553.