Drug Information

Drug (ID: DG00125) and It's Reported Resistant Information

• Name: Chloroquine
• Synonyms: Amokin; Aralen; Aralen HCl; Arechin; Arechine; Arequin; Arolen; Arthrochin; Artrichin; Avlochlor; Avloclor; Bemaco; Bemaphate; Bemasulph; Benaquin; Bipiquin; CU-01000012392-2; Capquin; Chemochin; Chingamin; Chloraquine; Chlorochin; Chlorochine; Chlorochinum; Chloroin; Chloroquin; Chloroquina; Chloroquine (USP/INN); Chloroquine (VAN); Chloroquine Bis-Phosphoric Acid; Chloroquine FNA (TN); Chloroquine [USAN:INN:BAN]; Chloroquine phosphate; Chloroquinium; Chloroquinum; Chloroquinum [INN-Latin]; Chlorquin; Cidanchin; Clorochina; Clorochina [DCIT]; Cloroquina; Cloroquina [INN-Spanish]; Cocartrit; Dawaquin (TN); Delagil; Dichinalex; Elestol; Gontochin; Gontochin phosphate; Heliopar; Imagon; Ipsen 225; Iroquine; Khingamin; Klorokin; Lapaquin; Malaquin; Malaquin (*Diphosphate*); Malaren; Malarex; Mesylith; Miniquine; Neochin; Nivachine; Nivaquine B; Pfizerquine; Quinachlor; Quinagamin; Quinagamine; Quinercyl; Quingamine; Quinilon; Quinoscan; RP 3377; RP-3377; Resochen; Resochin; Resochin (TN); Resoquina; Resoquine; Reumachlor; Reumaquin; Rivoquine; Ro 01-6014/N2; Ronaquine; Roquine; SN 6718; SN-7618; ST 21; ST 21 (pharmaceutical); Sanoquin; Silbesan;Siragan; Solprina; Sopaquin; Tanakan; Tanakene; Tresochin; Trochin; W 7618;WIN 244
• Indication:
  In total 1 Indication(s)
  Malaria [ICD-11: 1F45]; Approved; [1], [2], [3], [4]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Colorectal cancer [ICD-11: 2B91]; [5]
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Malaria [ICD-11: 1F45]; [6]
  Rheumatoid arthritis [ICD-11: FA20]; [7]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Astrocytoma [ICD-11: 2F36]; [8], [9], [10]
• Target: Duffy antigen chemokine receptor (ACKR1); ACKR1_HUMAN; [4]
• Formula: C18H26ClN3
• IsoSMILES: CCN(CC)CCCC(C)NC1=C2C=CC(=CC2=NC=C1)Cl
• InChI: 1S/C18H26ClN3/c1-4-22(5-2)12-6-7-14(3)21-17-10-11-20-18-13-15(19)8-9-16(17)18/h8-11,13-14H,4-7,12H2,1-3H3,(H,20,21)
• InChIKey: WHTVZRBIWZFKQO-UHFFFAOYSA-N
• PubChem CID: 2719
• ChEBI ID: CHEBI:3638
• TTD Drug ID: D09EGZ
• VARIDT ID: DR00572
• INTEDE ID: DR0301
• DrugBank ID: DB00608

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Fungal infection [ICD-11: 1F29-1F2F]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• 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
• In Vitro Model: Saccharomyces cerevisiae CH1305 (MAT a ade2 ade3 ura3 - 52 leu2 lys2 - 801 ); 4932
• In Vitro Model: Saccharomyces cerevisiae detaVma (MATa leu2deta met15deta ura3deta); 4932
• Experiment for Molecule Alteration: Western blot 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.

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

• Sensitive Disease: Fungal infection [ICD-11: 1F29-1F2F]
• 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
• In Vitro Model: Saccharomyces cerevisiae CH1305 (MAT a ade2 ade3 ura3 - 52 leu2 lys2 - 801 ); 4932
• In Vitro Model: Saccharomyces cerevisiae detaVma (MATa leu2deta met15deta ura3deta); 4932
• Experiment for Molecule Alteration: Western blot 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.

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

Colorectal cancer [ICD-11: 2B91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: . [5]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/beta-catenin Signalling Pathway; Regulation; N.A.
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The results showed that Huaier can regulate autophagy, inhibit the Wnt/-catenin signalling pathway and reverse the drug resistance of OXA-resistant CRC cells.

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) [1], [2], [3]

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

Key Molecule: Chloroquine resistance transporter (CRT) [8], [9], [10]

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

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4], [12], [13]

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

Key Molecule: Chloroquine resistance transporter (CRT) [2], [14], [15]

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

Key Molecule: Multidrug resistance protein 1 (ABCB1) [16], [17], [18]

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

Key Molecule: Chloroquine resistance transporter (CRT) [19], [20]

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

Key Molecule: Chloroquine resistance transporter (CRT) [19], [20]

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

Key Molecule: Chloroquine resistance transporter (CRT) [9], [20]

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

Key Molecule: Chloroquine resistance transporter (CRT) [9], [20]

• 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 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.

Key Molecule: Chloroquine resistance transporter (CRT) [9], [20]

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

Key Molecule: Chloroquine resistance transporter (CRT) [9], [20]

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

Key Molecule: Chloroquine resistance transporter (CRT) [21]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• 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
• In Vitro Model: Plasmodium falciparum Dd2; 5833
• In Vitro Model: Plasmodium falciparum PfCRT; 5833
• Experiment for Molecule Alteration: Western blot 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.

Key Molecule: Chloroquine resistance transporter (CRT) [22]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.C101
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum isolate 3D7; 5833
• In Vitro Model: Plasmodium falciparum isolate 7G8; 5833
• In Vitro Model: Plasmodium falciparum isolate Dd2; 5833
• Experiment for Molecule Alteration: Western blot 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.

Key Molecule: Chloroquine resistance transporter (CRT) [22]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.L272F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum isolate 3D7; 5833
• In Vitro Model: Plasmodium falciparum isolate 7G8; 5833
• In Vitro Model: Plasmodium falciparum isolate Dd2; 5833
• Experiment for Molecule Alteration: Western blot 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.

Key Molecule: Chloroquine resistance transporter (CRT) [2]

• Resistant 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 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.

Key Molecule: Chloroquine resistance transporter (CRT) [2]

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

Key Molecule: Chloroquine resistance transporter (CRT) [2]

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

Key Molecule: Chloroquine resistance transporter (CRT) [2]

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

Key Molecule: Chloroquine resistance transporter (CRT) [2]

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

Key Molecule: Chloroquine resistance transporter (CRT) [20]

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

Key Molecule: Chloroquine resistance transporter (CRT) [20]

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

Key Molecule: Chloroquine resistance transporter (CRT) [20]

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

Key Molecule: Multidrug resistance protein 1 (ABCB1) [12]

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

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

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

Key Molecule: Chloroquine resistance transporter (CRT) [23]

• 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 at Ser-33 and Ser-411 of PfCRT of the chloroquine-resistant P. falciparum strain Dd2 and kinase inhibitors can sensitize drug responsiveness.

Key Molecule: Putative chloroquine resistance transporter (PVCRT) [24]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.K10 insertion (c.AAG)
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Mutations in k10 insertion in the Pvcrt-o gene have been identified as a possible molecular marker of CQ resistance in P.vivax.

Key Molecule: Putative chloroquine resistance transporter (PVCRT) [24]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.K10 insertion (c.AAG)
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax isolates; 5855
• Experiment for Molecule Alteration: Nested PCR
• Mechanism Description: Mutations in k10 insertion in the Pvcrt-o gene have been identified as a possible molecular marker of CQ resistance in P.vivax.

Key Molecule: Putative chloroquine resistance transporter (PVCRT) [25]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.S249P
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast CH1305; 4932
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Quantitative Growth Rate assay
• Mechanism Description: It is surprising then that the data presented here suggests a single mutation (S249P in PvCRT isoform CQR3) can increase CQ transport by 32% relative to wild type.

Key Molecule: Chloroquine resistance transporter (CRT) [19]

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

Key Molecule: Chloroquine resistance transporter (CRT) [19]

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

Key Molecule: Chloroquine resistance transporter (CRT) [19]

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

Key Molecule: Chloroquine resistance transporter (CRT) [26]

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

Key Molecule: Chloroquine resistance transporter (CRT) [26]

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

Key Molecule: Chloroquine resistance transporter (CRT) [27]

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

Key Molecule: Putative chloroquine resistance transporter (PVCRT) [28]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax strains; 5855
• Mechanism Description: Patients with CQ-resistant P. vivax parasites presented a higher gene expression of pvcrt-o and pvmdr-1 at D0 and DR when compared to the susceptible group. For the CQR patients, median gene expression values at D0 and DR, presented 2.4 fold (95% CI: 0.96-7.1) and 6.1 fold (95% CI: 3.8-14.3) increase in pvcrt-o levels compared to the susceptible patients at D0 with 0.12 fold (95% CI: 0.034-0.324). Median gene expression for pvmdr-1 presented 2.0 fold (95% CI: 0.95-3.8) and 2.4 fold (95% CI: 0.53-9.1) increase levels at D0 and DR, for the CQR patients versus 0.288 fold (95% CI: 0.068-0.497) for the susceptible patients.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [28]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax strains; 5855
• Mechanism Description: Patients with CQ-resistant P. vivax parasites presented a higher gene expression of pvcrt-o and pvmdr-1 at D0 and DR when compared to the susceptible group. For the CQR patients, median gene expression values at D0 and DR, presented 2.4 fold (95% CI: 0.96-7.1) and 6.1 fold (95% CI: 3.8-14.3) increase in pvcrt-o levels compared to the susceptible patients at D0 with 0.12 fold (95% CI: 0.034-0.324). Median gene expression for pvmdr-1 presented 2.0 fold (95% CI: 0.95-3.8) and 2.4 fold (95% CI: 0.53-9.1) increase levels at D0 and DR, for the CQR patients versus 0.288 fold (95% CI: 0.068-0.497) for the susceptible patients.

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

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.K76T
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum C-1Dd2; 5833
• In Vitro Model: Plasmodium falciparum C2GC03; 5833
• In Vitro Model: Plasmodium falciparum C3Dd2; 5833
• In Vitro Model: Plasmodium falciparum C67G8; 5833
• In Vitro Model: Plasmodium falciparum GC03; 5833
• In Vitro Model: Plasmodium falciparum T76k-1Dd2; 5833
• Experiment for Molecule Alteration: Western blot 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.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [29]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.976F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax isolates; 5855
• Mechanism Description: In Southeast Asia the pvmdr1 976 F allele has been associated with reduced susceptibility to CQ. Finding the pvmdr1 976 F allele in 7/41 (17%) P. vivax might thus indicate a degree of CQ tolerance but probably not resistance in Honduras.

Key Molecule: Chloroquine resistance transporter (CRT) [16]

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

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

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

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

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

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

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

Key Molecule: Chloroquine resistance transporter (CRT) [30], [31]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Human foreskin fibroblasts; N.A.; Saccharomyces cerevisiae; N.A.
• In Vitro Model: Toxoplasma gondii Prudetaku80S/Luc; 1080348
• In Vivo Model: C57BL/6J mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tachyzoite plaque assay
• Mechanism Description: Rrecombinant PfCRT transports amino acids, small peptides, and chloroquine, suggests that PfCRT functions to transport products of hemoglobin digestion out of the digestive vacuole. TgCRT is also able to transport amino acids and small peptides out of the VAC. TgCRT-deficient tachyzoites also grow more slowly in vitro and are compromised in their ability to cause mortality in mice during acute infection, suggesting that an inability to transport digested material out of the VAC and into the parasite cytosol has a moderate effect on T. gondii tachyzoites.

Key Molecule: Chloroquine resistance transporter (CRT) [32], [33], [34]

• 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
• Experiment for Molecule Alteration: Western blot 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.

Key Molecule: Chloroquine resistance transporter (CRT) [35]

• 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) [36]

• 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 3D7; 36329
• In Vitro Model: 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.

Key Molecule: Chloroquine resistance transporter (CRT) [36]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.L272F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum 3D7; 36329
• In Vitro Model: 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.

Key Molecule: Chloroquine resistance transporter (CRT) [33]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.S163R
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Plasmodium falciparum D10; 5833
• In Vitro Model: Plasmodium falciparum Dd2; 5833
• In Vitro Model: 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.

Key Molecule: Chloroquine resistance transporter (CRT) [33]

• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Molecule Alteration: Missense mutation; p.T76K
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Plasmodium falciparum D10; 5833
• In Vitro Model: Plasmodium falciparum Dd2; 5833
• In Vitro Model: 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.

Key Molecule: ABC transporter (ABCT) [32]

• 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: Phenothiazine drugs (chlor-promazine, trifluoperazine, prochlorperazine, methotrime-prazin or fluphenazin) can enhance in vitro the potency of CQ against P. falciparum CQ-resistant strains. phenothiazines may exert their CQ resistance reversal activity by interacting with Pgh1. Combinations of chlorpromazine or prochlorperazine with CQ confirm the reversal effect of these drugs on the CQ resistance as showed by cures obtained in Aotus monkeys infected with CQ-resistant P. falciparum.

ICD-15: Musculoskeletal/connective-tissue diseases

Rheumatoid arthritis [ICD-11: FA20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

References

• Ref 1: Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine. Nat Commun. 2018 Aug 17;9(1):3314. doi: 10.1038/s41467-018-05652-0.
• Ref 2: Prevalence of mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, and association with ex vivo susceptibility to common anti-malarial drugs against African Plasmodium falciparum isolates. Malar J. 2020 Jun 5;19(1):201. doi: 10.1186/s12936-020-03281-x.
• Ref 3: Distribution and Temporal Dynamics of Plasmodium falciparum Chloroquine Resistance Transporter Mutations Associated With Piperaquine Resistance in Northern Cambodia. J Infect Dis. 2021 Sep 17;224(6):1077-1085. doi: 10.1093/infdis/jiab055.
• Ref 4: 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 5: Huaier Regulates Oxaliplatin Resistance in Colorectal Cancer by Regulating Autophagy and Inhibiting the Wnt/beta-catenin Signalling Pathway. Front Biosci (Landmark Ed). 2024 Jan 17;29(1):15.
• Ref 6: Epidemiology, drug resistance, and pathophysiology of Plasmodium vivax malariaJ Vector Borne Dis. 2018 Jan-Mar;55(1):1-8. doi: 10.4103/0972-9062.234620.
• Ref 7: Drug-resistance in rheumatoid arthritis: the role of p53 gene mutations, ABC family transporters and personal factors .Curr Opin Pharmacol. 2020 Oct;54:59-71. doi: 10.1016/j.coph.2020.08.002. Epub 2020 Sep 14. 10.1016/j.coph.2020.08.002
• Ref 8: The malaria parasite's chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily. Mol Biol Evol. 2004 Oct;21(10):1938-49. doi: 10.1093/molbev/msh205. Epub 2004 Jul 7.
• Ref 9: Sequence and gene expression of chloroquine resistance transporter (pfcrt) in the association of in vitro drugs resistance of Plasmodium falciparum. Malar J. 2011 Feb 15;10:42. doi: 10.1186/1475-2875-10-42.
• Ref 10: Glutathione transport: a new role for PfCRT in chloroquine resistance. Antioxid Redox Signal. 2013 Sep 1;19(7):683-95. doi: 10.1089/ars.2012.4625. Epub 2012 Dec 20.
• Ref 11: Plasmodium falciparum chloroquine resistance transporter (PfCRT) isoforms PH1 and PH2 perturb vacuolar physiology. Malar J. 2016 Mar 31;15:186. doi: 10.1186/s12936-016-1238-1.
• Ref 12: 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 13: 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 14: Structure and drug resistance of the Plasmodium falciparum transporter PfCRT. Nature. 2019 Dec;576(7786):315-320. doi: 10.1038/s41586-019-1795-x. Epub 2019 Nov 27.
• Ref 15: Altered Drug Transport by Plasmodium falciparum Chloroquine Resistance Transporter Isoforms Harboring Mutations Associated with Piperaquine Resistance. Biochemistry. 2020 Jul 14;59(27):2484-2493. doi: 10.1021/acs.biochem.0c00247. Epub 2020 Jul 1.
• Ref 16: 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 17: 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 18: 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 19: Mutational prevalence of chloroquine resistance transporter gene among Plasmodium falciparum field isolates in Assam and Arunachal Pradesh, India. Indian J Med Microbiol. 2016 Apr-Jun;34(2):193-7. doi: 10.4103/0255-0857.180298.
• Ref 20: Structural and evolutionary analyses of the Plasmodium falciparum chloroquine resistance transporter. Sci Rep. 2020 Mar 16;10(1):4842. doi: 10.1038/s41598-020-61181-1.
• Ref 21: Molecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria. Annu Rev Microbiol. 2020 Sep 8;74:431-454. doi: 10.1146/annurev-micro-020518-115546.
• Ref 22: The natural function of the malaria parasite's chloroquine resistance transporter. Nat Commun. 2020 Aug 6;11(1):3922. doi: 10.1038/s41467-020-17781-6.
• Ref 23: Phosphomimetic substitution at Ser-33 of the chloroquine resistance transporter PfCRT reconstitutes drug responses in Plasmodium falciparum. J Biol Chem. 2019 Aug 23;294(34):12766-12778. doi: 10.1074/jbc.RA119.009464. Epub 2019 Jul 8.
• Ref 24: Distribution of Mutations Associated with Antifolate and Chloroquine Resistance among Imported Plasmodium vivax in the State of Qatar. Am J Trop Med Hyg. 2017 Dec;97(6):1797-1803. doi: 10.4269/ajtmh.17-0436. Epub 2017 Sep 28.
• Ref 25: Analysis of Plasmodium vivax Chloroquine Resistance Transporter Mutant Isoforms. Biochemistry. 2017 Oct 17;56(41):5615-5622. doi: 10.1021/acs.biochem.7b00749. Epub 2017 Sep 26.
• Ref 26: Verapamil-Sensitive Transport of Quinacrine and Methylene Blue via the Plasmodium falciparum Chloroquine Resistance Transporter Reduces the Parasite's Susceptibility to these Tricyclic Drugs. J Infect Dis. 2016 Mar 1;213(5):800-10. doi: 10.1093/infdis/jiv509. Epub 2015 Oct 26.
• Ref 27: Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter. Mol Microbiol. 2015 Jul;97(2):381-95. doi: 10.1111/mmi.13035. Epub 2015 May 20.
• Ref 28: Expression levels of pvcrt-o and pvmdr-1 are associated with chloroquine resistance and severe Plasmodium vivax malaria in patients of the Brazilian Amazon. PLoS One. 2014 Aug 26;9(8):e105922. doi: 10.1371/journal.pone.0105922. eCollection 2014.
• Ref 29: Drug resistance associated genetic polymorphisms in Plasmodium falciparum and Plasmodium vivax collected in Honduras, Central America. Malar J. 2011 Dec 19;10:376. doi: 10.1186/1475-2875-10-376.
• Ref 30: Characterization of the chloroquine resistance transporter homologue in Toxoplasma gondii. Eukaryot Cell. 2014 Nov;13(11):1360-70. doi: 10.1128/EC.00027-14. Epub 2014 May 23.
• Ref 31: Role of Toxoplasma gondii Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance. mBio. 2019 Aug 6;10(4):e01324-19. doi: 10.1128/mBio.01324-19.
• Ref 32: Inhibition of efflux of quinolines as new therapeutic strategy in malaria. Curr Top Med Chem. 2008;8(7):563-78. doi: 10.2174/156802608783955593.
• Ref 33: Chloroquine transport via the malaria parasite's chloroquine resistance transporter. Science. 2009 Sep 25;325(5948):1680-2. doi: 10.1126/science.1175667.
• Ref 34: Saquinavir inhibits the malaria parasite's chloroquine resistance transporter. Antimicrob Agents Chemother. 2012 May;56(5):2283-9. doi: 10.1128/AAC.00166-12. Epub 2012 Feb 21.
• Ref 35: A Variant PfCRT Isoform Can Contribute to Plasmodium falciparum Resistance to the First-Line Partner Drug Piperaquine. mBio. 2017 May 9;8(3):e00303-17. doi: 10.1128/mBio.00303-17.
• Ref 36: Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities. Sci Rep. 2015 Sep 30;5:14552. doi: 10.1038/srep14552.