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Gene Review

PfMDR1  -  multidrug resistance protein

Plasmodium falciparum 3D7

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Disease relevance of PFMDR1

  • Widespread introduction of artemisinin derivatives in the treatment of falciparum malaria may prevent the spread of multidrug resistance [1].
  • The spread of multidrug resistance in the most pathogenic causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory properties [2].
  • The clinical efficacy of these drugs is characterized by an almost immediate onset and rapid reduction of parasitemia, and it is high in such areas as well where multidrug-resistance is rampant [3].
  • Although long term studies of drug safety are not yet available, doxycycline and mefloquine appear to be the drugs of choice in areas where P. falciparum shows multidrug resistance [4].

High impact information on PFMDR1


Chemical compound and disease context of PFMDR1

  • Multidrug resistance of Plasmodium falciparum is spreading throughout Africa. In Lambarene, Gabon where chloroquine-resistant malaria is prevalent, a randomized comparative trial with three regimens for treating P. falciparum malaria in adults was performed [9].

Biological context of PFMDR1


Associations of PFMDR1 with chemical compounds

  • Concomitant with the increase in mefloquine resistance was a corresponding increase in the level of resistance to halofantrine and quinine, suggesting a true multidrug-resistance phenotype [14].
  • However, given the history of the development of resistance to other antimalarial drugs, the use of artesunate should be restricted to areas of multidrug resistance, the drug should be used in combination with a longer acting agent such as mefloquine, and it should be used in regimens that provide radical cure rates of 90 to 100% [15].
  • Using direct sequencing of PCR products, we have analyzed sequence polymorphism of the dihydrofolate reductase-thymidylate synthase, dihydropteroate synthetase, and multidrug resistance 1 genes in a large number of clinical P. falciparum isolates collected in various areas of Cambodia [16].
  • Furthermore, the expression of the mdr-like mRNAs was increased 3-4 times when clone C2 mutants were grown under drug pressure vs. the same parasites grown without emetine [11].
  • It is postulated that these lipophilic drugs are interacting with the mechanism of resistance, possibly a multidrug resistance glycoprotein pump [17].

Analytical, diagnostic and therapeutic context of PFMDR1


  1. Effects of artemisinin derivatives on malaria transmissibility. Price, R.N., Nosten, F., Luxemburger, C., ter Kuile, F.O., Paiphun, L., Chongsuphajaisiddhi, T., White, N.J. Lancet (1996) [Pubmed]
  2. Targeting tuberculosis and malaria through inhibition of Enoyl reductase: compound activity and structural data. Kuo, M.R., Morbidoni, H.R., Alland, D., Sneddon, S.F., Gourlie, B.B., Staveski, M.M., Leonard, M., Gregory, J.S., Janjigian, A.D., Yee, C., Musser, J.M., Kreiswirth, B., Iwamoto, H., Perozzo, R., Jacobs, W.R., Sacchettini, J.C., Fidock, D.A. J. Biol. Chem. (2003) [Pubmed]
  3. Recent advances in artemisinin and its derivatives as antimalarial and antitumor agents. Jung, M., Lee, K., Kim, H., Park, M. Current medicinal chemistry. (2004) [Pubmed]
  4. Prevention of malaria. Keystone, J.S. Drugs (1990) [Pubmed]
  5. Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of P. falciparum. Foote, S.J., Thompson, J.K., Cowman, A.F., Kemp, D.J. Cell (1989) [Pubmed]
  6. Biophysical aspects of P-glycoprotein-mediated multidrug resistance. Wadkins, R.M., Roepe, P.D. Int. Rev. Cytol. (1997) [Pubmed]
  7. A comparison of the phenomenology and genetics of multidrug resistance in cancer cells and quinoline resistance in Plasmodium falciparum. Bray, P.G., Ward, S.A. Pharmacol. Ther. (1998) [Pubmed]
  8. Malaria parasites can develop stable resistance to artemisinin but lack mutations in candidate genes atp6 (encoding the sarcoplasmic and endoplasmic reticulum Ca2+ ATPase), tctp, mdr1, and cg10. Afonso, A., Hunt, P., Cheesman, S., Alves, A.C., Cunha, C.V., do Rosário, V., Cravo, P. Antimicrob. Agents Chemother. (2006) [Pubmed]
  9. Comparison of micronized halofantrine with chloroquine-antibiotic combinations for treating Plasmodium falciparum malaria in adults from Gabon. Kremsner, P.G., Wildling, E., Jenne, L., Graninger, W., Bienzle, U. Am. J. Trop. Med. Hyg. (1994) [Pubmed]
  10. Identification of the Plasmodium vivax mdr-like gene (pvmdr1) and analysis of single-nucleotide polymorphisms among isolates from different areas of endemicity. Brega, S., Meslin, B., de Monbrison, F., Severini, C., Gradoni, L., Udomsangpetch, R., Sutanto, I., Peyron, F., Picot, S. J. Infect. Dis. (2005) [Pubmed]
  11. Emetine-resistant mutants of Entamoeba histolytica overexpress mRNAs for multidrug resistance. Samuelson, J., Ayala, P., Orozco, E., Wirth, D. Mol. Biochem. Parasitol. (1990) [Pubmed]
  12. In vitro susceptibility of Plasmodium falciparum isolates from Myanmar to antimalarial drugs. Wongsrichanalai, C., Lin, K., Pang, L.W., Faiz, M.A., Noedl, H., Wimonwattrawatee, T., Laoboonchai, A., Kawamoto, F. Am. J. Trop. Med. Hyg. (2001) [Pubmed]
  13. Chloroquine resistance in Plasmodium chabaudi: are chloroquine-resistance transporter (crt) and multi-drug resistance (mdr1) orthologues involved? Hunt, P., Cravo, P.V., Donleavy, P., Carlton, J.M., Walliker, D. Mol. Biochem. Parasitol. (2004) [Pubmed]
  14. Selection for mefloquine resistance in Plasmodium falciparum is linked to amplification of the pfmdr1 gene and cross-resistance to halofantrine and quinine. Cowman, A.F., Galatis, D., Thompson, J.K. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  15. Artesunate. A review of its pharmacology and therapeutic efficacy in the treatment of malaria. Barradell, L.B., Fitton, A. Drugs (1995) [Pubmed]
  16. Countrywide survey shows very high prevalence of Plasmodium falciparum multilocus resistance genotypes in Cambodia. Khim, N., Bouchier, C., Ekala, M.T., Incardona, S., Lim, P., Legrand, E., Jambou, R., Doung, S., Puijalon, O.M., Fandeur, T. Antimicrob. Agents Chemother. (2005) [Pubmed]
  17. Reversal of chloroquine resistance in falciparum malaria independent of calcium channels. Ye, Z.G., Van Dyke, K. Biochem. Biophys. Res. Commun. (1988) [Pubmed]
  18. Lack of prediction of mefloquine and mefloquine-artesunate treatment outcome by mutations in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene for P. falciparum malaria in Peru. Pillai, D.R., Hijar, G., Montoya, Y., Marouiño, W., Ruebush, T.K., Wongsrichanalai, C., Kain, K.C. Am. J. Trop. Med. Hyg. (2003) [Pubmed]
  19. Molecular epidemiology of malaria in Yaoundé, Cameroon. III. Analysis of chloroquine resistance and point mutations in the multidrug resistance 1 (pfmdr 1) gene of Plasmodium falciparum. Basco, L.K., Ringwald, P. Am. J. Trop. Med. Hyg. (1998) [Pubmed]
  20. Plasmodium falciparum: detection of P-glycoprotein in chloroquine-susceptible and chloroquine-resistant clones and isolates. Cremer, G., Basco, L.K., Le Bras, J., Camus, D., Slomianny, C. Exp. Parasitol. (1995) [Pubmed]
  21. Antimalarial combinations. Kremsner, P.G., Krishna, S. Lancet (2004) [Pubmed]
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