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Genetic and genomic approaches for the discovery of parasite genes involved in antimalarial drug resistance

Published online by Cambridge University Press:  09 August 2013

JONATHAN M. MWANGI  and
LISA C. RANFORD-CARTWRIGHT
JONATHAN M. MWANGI*
Affiliation:
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, Scotland, UK
LISA C. RANFORD-CARTWRIGHT
Affiliation:
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, Scotland, UK
*
*Corresponding author: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, Scotland, UK. Tel: +44 141 330 4426. Fax: +44 141 330 4600. E-mail: [email protected]
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Summary

The biggest threat to the war on malaria is the continued evolution of drug resistance by the parasite. Resistance to almost all currently available antimalarials now exists in Plasmodium falciparum which causes the most suffering among all human malaria parasites. Monitoring of antimalarial efficacy and the development and subsequent spread of resistance has become an important part in the treatment and control of malaria. With recent reports of reduced efficacy of artemisinin, the current recommended treatment for uncomplicated malaria, there is urgent need for better methods to recognize and monitor drug resistance for effective treatment. Molecular markers have become a welcome addition to complement the more laborious and costly in vitro and in vivo methods that have traditionally been used to monitor drug resistance. However, there are currently no molecular markers for resistance to some antimalarials. This review highlights the role of the various genetic and genomic approaches that have been used in identifying the molecular markers that underlie drug resistance in P. falciparum. These approaches include; candidate genes, genetic linkage and genome-wide association studies. We discuss the requirements and limitations of each approach and use various examples to illustrate their contributions in identifying genomic regions of the parasite associated with antimalarial drug responses.

Keywords

Candidate genedrug resistancegenome-wide associationlinkage analysismalariamolecular markersPlasmodium falciparum
Type
Research Article
Information
Parasitology , Volume 140 , Issue 12: Genetic and genomic approaches to understanding drug resistance in parasites , October 2013 , pp. 1455 - 1467
Copyright
Copyright © Cambridge University Press 2013 

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References

REFERENCES

Anderson, T. J., Nair, S., Nkhoma, S., Williams, J. T., Imwong, M., Yi, P., Socheat, D., Das, D., Chotivanich, K., Day, N. P., White, N. J. and Dondorp, A. M. (2010). High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia. Journal of Infectious Diseases 201, 1326–1330. doi: 10.1086/651562.CrossRefGoogle ScholarPubMed
Anderson, T. J. and Roper, C. (2005). The origins and spread of antimalarial drug resistance: lessons for policy makers. Acta Tropica 94, 269–280. doi: S0001-706X(05)00079-3 [pii]; doi: 10.1016/j.actatropica.2005.04.010.CrossRefGoogle ScholarPubMed
Anfinsen, C. B. (1947). The inhibitory action of naphthoquinones on respiratory process; the inhibition of cleavage and respiration in the eggs of Arbacia punctulata. Journal of Cellular Physiology 29, 323–332.CrossRefGoogle ScholarPubMed
Avery, J. S. (1958). Mass treatment with pyrimethamine: a study of resistance and cross resistance resulting from a field trial in a hyperendemic malarious area of Makueni, Kenya. September 1952–September 1953. Transactions of the Royal Society of Tropical Medicine and Hygiene 52, 547–561.CrossRefGoogle Scholar
Awad-el-Kariem, F. M., Miles, M. A. and Warhurst, D. C. (1992). Chloroquine-resistant Plasmodium falciparum isolates from the Sudan lack two mutations in the pfmdr1 gene thought to be associated with chloroquine resistance. Transactions of the Royal Society of Tropical Medicine and Hygiene 86, 587–589.CrossRefGoogle ScholarPubMed
Babiker, H. A., Pringle, S. J., Abdel-Muhsin, A., Mackinnon, M., Hunt, P. and Walliker, D. (2001). High-level chloroquine resistance in Sudanese isolates of Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene pfcrt and the multidrug resistance Gene pfmdr1. Journal of Infectious Diseases 183, 1535–1538. doi: JID001320 [pii]; doi: 10.1086/320195.CrossRefGoogle ScholarPubMed
Ball, E. G., Anfinsen, C. B. and Cooper, O. (1947). The inhibitory action of naphthoquinones on respiratory processes. Journal of Biological Chemistry 168, 257–270.CrossRefGoogle ScholarPubMed
Basco, L. K., de Pecoulas, P. E., le, B. J. and Wilson, C. M. (1996). Plasmodium falciparum: molecular characterization of multidrug-resistant Cambodian isolates. Experimental Parasitology 82, 97–103. doi: S0014-4894(96)90013-2 [pii]; doi: 10.1006/expr.1996.0013.CrossRefGoogle ScholarPubMed
Basco, L. K., le, B. J., Rhoades, Z. and Wilson, C. M. (1995). Analysis of pfmdr1 and drug susceptibility in fresh isolates of Plasmodium falciparum from subsaharan Africa. Molecular and Biochemical Parasitology 74, 157–166. doi: 0166685195024921 [pii].CrossRefGoogle ScholarPubMed
Bennett, T. N., Kosar, A. D., Ursos, L. M., Dzekunov, S., Singh Sidhu, A. B., Fidock, D. A. and Roepe, P. D. (2004). Drug resistance-associated pfCRT mutations confer decreased Plasmodium falciparum digestive vacuolar pH. Molecular and Biochemical Parasitology 133, 99–114. doi: S0166685103002792 [pii].CrossRefGoogle ScholarPubMed
Bloland, P. B. (2001). Drug Resistant Malaria. World Health Organization, Geneva, Switzerland.Google Scholar
Bosia, A., Ghigo, D., Turrini, F., Nissani, E., Pescarmona, G. P. and Ginsburg, H. (1993). Kinetic characterization of Na+/H+ antiport of Plasmodium falciparum membrane. Journal of Cellular Physiology 154, 527–534. doi: 10.1002/jcp.1041540311.CrossRefGoogle ScholarPubMed
Bottius, E., Guanzirolli, A., Trape, J. F., Rogier, C., Konate, L. and Druilhe, P. (1996). Malaria: even more chronic in nature than previously thought; Evidence for subpatent parasitaemia detectable by the polymerase chain reaction. Transactions of the Royal Society of Tropical Medicine and Hygiene 90, 15–19.CrossRefGoogle ScholarPubMed
Bouchaud, O., Imbert, P., Touze, J. E., Dodoo, A. N., Danis, M. and Legros, F. (2009). Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base. Malaria Journal 8, 289-1475-2875-8-289 [pii]; doi: 10.1186/1475-2875-8-289.CrossRefGoogle ScholarPubMed
Bray, P. G., Mungthin, M., Ridley, R. G. and Ward, S. A. (1998). Access to hematin: the basis of chloroquine resistance. Molecular Pharmacology 54, 170–179.CrossRefGoogle ScholarPubMed
Briolant, S., Pelleau, S., Bogreau, H., Hovette, P., Zettor, A., Castello, J., Baret, E., Amalvict, R., Rogier, C. and Pradines, B. (2011). In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger (Pfnhe-1) gene: the absence of association in clinical isolates from the Republic of Congo. Malaria Journal 10, 37-1475-2875-10-37 [pii]; doi: 10.1186/1475-2875-10-37.CrossRefGoogle ScholarPubMed
Bruce-Chwatt, L. J. (1956). Chemotherapy in relation to possibilities of malaria eradication in tropical Africa. Bulletin of the World Health Organization 15, 852–862.Google ScholarPubMed
Bruce-Chwatt, L. J. (1988). Three hundred and fifty years of the Peruvian fever bark. British Medical Journal (Clinical Research Edition) 296, 1486–1487.CrossRefGoogle ScholarPubMed
Campbell, C. C., Chin, W., Collins, W. E., Teutsch, S. M. and Moss, D. M. (1979). Chloroquine-resistant Plasmodium falciparum from East Africa: cultivation and drug sensitivity of the Tanzanian I/CDC strain from an American tourist. Lancet 2, 1151–1154.CrossRefGoogle ScholarPubMed
Cheeseman, I. H., Miller, B. A., Nair, S., Nkhoma, S., Tan, A., Tan, J. C., Al, S. S., Phyo, A. P., Moo, C. L., Lwin, K. M., McGready, R., Ashley, E., Imwong, M., Stepniewska, K., Yi, P., Dondorp, A. M., Mayxay, M., Newton, P. N., White, N. J., Nosten, F., Ferdig, M. T. and Anderson, T. J. (2012). A major genome region underlying artemisinin resistance in malaria. Science 336, 79–82. doi: 336/6077/79 [pii]; doi: 10.1126/science.1215966.CrossRefGoogle Scholar
Chen, N., Kyle, D. E., Pasay, C., Fowler, E. V., Baker, J., Peters, J. M. and Cheng, Q. (2003). pfcrt Allelic types with two novel amino acid mutations in chloroquine-resistant Plasmodium falciparum isolates from the Philippines. Antimicrobial Agents and Chemotherapy 47, 3500–3505.CrossRefGoogle ScholarPubMed
Chiodini, P. L., Conlon, C. P., Hutchinson, D. B. A., Farquhar, J. A., Hall, A. P., Peto, T. E. A., Birley, H. and Warrell, D. A. (1995). Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria. Journal of Antimicrobial Chemotherapy 36, 1073–1078.CrossRefGoogle ScholarPubMed
Chou, A. C., Chevli, R. and Fitch, C. D. (1980). Ferriprotoporphyrin IX fulfills the criteria for identification as the chloroquine receptor of malaria parasites. Biochemistry 19, 1543–1549.CrossRefGoogle ScholarPubMed
Coatney, G. R., Myatt, A. V., Hernandez, T., Jeffery, G. M. and Cooper, W. C. (1952). Studies on the compound 50–63. Transactions of the Royal Society of Tropical Medicine and Hygiene 46, 496–497.CrossRefGoogle ScholarPubMed
Codd, A., Teuscher, F., Kyle, D. E., Cheng, Q. and Gatton, M. L. (2011). Artemisinin-induced parasite dormancy: a plausible mechanism for treatment failure. Malaria Journal 10, 56-1475-2875-10-56 [pii]; doi: 10.1186/1475-2875-10-56.CrossRefGoogle ScholarPubMed
Conway, D. J., Greenwood, B. M. and McBride, J. S. (1991). The epidemiology of multiple-clone Plasmodium falciparum infections in Gambian patients. Parasitology 103(Pt 1), 1–6.CrossRefGoogle ScholarPubMed
Cooper, R. A., Ferdig, M. T., Su, X. Z., Ursos, L. M., Mu, J., Nomura, T., Fujioka, H., Fidock, D. A., Roepe, P. D. and Wellems, T. E. (2002). Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses in Plasmodium falciparum. Molecular Pharmacology 61, 35–42.CrossRefGoogle ScholarPubMed
Cooper, R. A., Hartwig, C. L. and Ferdig, M. T. (2005). pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective. Acta Tropica 94, 170–180. doi: S0001-706X(05)00085-9 [pii]; doi: 10.1016/j.actatropica.2005.04.004.CrossRefGoogle Scholar
Cowman, A. F. and Karcz, S. R. (1991). The pfmdr gene homologues of Plasmodium falciparum. Acta Leiden 60, 121–129.Google ScholarPubMed
Cowman, A. F., Morry, M. J., Biggs, B. A., Cross, G. A. and Foote, S. J. (1988). Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proceedings of the National Academy of Sciences, USA 85, 9109–9113.CrossRefGoogle ScholarPubMed
Cox-Singh, J., Singh, B., Alias, A. and Abdullah, M. S. (1995). Assessment of the association between three pfmdr1 point mutations and chloroquine resistance in vitro of Malaysian Plasmodium falciparum isolates. Transactions of the Royal Society of Tropical Medicine and Hygiene 89, 436–437.CrossRefGoogle ScholarPubMed
Crabb, B. S., Rug, M., Gilberger, T. W., Thompson, J. K., Triglia, T., Maier, A. G. and Cowman, A. F. (2004). Transfection of the human malaria parasite Plasmodium falciparum. Methods in Molecular Biology 270, 263–276. doi: 1-59259-793-9:263 [pii]; doi: 10.1385/1-59259-793-9:263.Google ScholarPubMed
Curd, F. H., Davey, D. G. and Rose, F. L. (1945). Studies on synthetic antimalarial drugs; some biguanide derivatives as new types of antimalarial substances with both therapeutic and causal prophylactic activity. Annals of Tropical Medicine and Parasitology 39, 208–216.CrossRefGoogle ScholarPubMed
Curtis, C. F. and Otoo, L. N. (1986). A simple model of the build-up of resistance to mixtures of anti-malarial drugs. Transactions of the Royal Society of Tropical Medicine and Hygiene 80, 889–892.CrossRefGoogle ScholarPubMed
Diggens, S. M., Gutteridge, W. E. and Trigg, P. I. (1970). Altered dihydrofolate reductase associated with a pyrimethamine-resistant Plasmodium berghei berghei produced in a single step. Nature 228, 579–580.CrossRefGoogle Scholar
Djimde, A., Doumbo, O. K., Cortese, J. F., Kayentao, K., Doumbo, S., Diourte, Y., Coulibaly, D., Dicko, A., Su, X. Z., Nomura, T., Fidock, D. A., Wellems, T. E. and Plowe, C. V. (2001). A molecular marker for chloroquine-resistant falciparum malaria. New England Journal of Medicine 344, 257–263. doi: 10.1056/NEJM200101253440403.CrossRefGoogle ScholarPubMed
Dondorp, A. M., Newton, P. N., Mayxay, M., Van, D. W., Smithuis, F. M., Yeung, S., Petit, A., Lynam, A. J., Johnson, A., Hien, T. T., McGready, R., Farrar, J. J., Looareesuwan, S., Day, N. P., Green, M. D. and White, N. J. (2004). Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials. Tropical Medicine and International Health 9, 1241–1246. doi: TMI1342 [pii]; 10.1111/j.1365-3156.2004.01342.x.CrossRefGoogle Scholar
Dondorp, A. M., Nosten, F., Yi, P., Das, D., Phyo, A. P., Tarning, J., Lwin, K. M., Ariey, F., Hanpithakpong, W., Lee, S. J., Ringwald, P., Silamut, K., Imwong, M., Chotivanich, K., Lim, P., Herdman, T., An, S. S., Yeung, S., Singhasivanon, P., Day, N. P., Lindegardh, N., Socheat, D. and White, N. J. (2009). Artemisinin resistance in Plasmodium falciparum malaria. New England Journal of Medicine 361, 455–467. doi: 361/5/455 [pii]; 10.1056/NEJMoa0808859.CrossRefGoogle ScholarPubMed
Dorn, A., Vippagunta, S. R., Matile, H., Jaquet, C., Vennerstrom, J. L. and Ridley, R. G. (1998). An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials. Biochemical Pharmacology 55, 727–736. doi: S0006-2952(97)00510-8 [pii].CrossRefGoogle ScholarPubMed
Duraisingh, M. T., Jones, P., Sambou, I., von, S. L., Pinder, M. and Warhurst, D. C. (2000). The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin. Molecular and Biochemical Parasitology 108, 13–23. doi: S0166-6851(00)00201-2 [pii].CrossRefGoogle Scholar
Eyles, D. E., Hoo, C. C., Warren, M. and Sandosham, A. A. (1963). Plasmodium falciparum resistant to chloroquine in Cambodia. American Journal of Tropical Medicine and Hygiene 12, 840–843.CrossRefGoogle ScholarPubMed
Ferdig, M. T., Cooper, R. A., Mu, J., Deng, B., Joy, D. A., Su, X. Z. and Wellems, T. E. (2004). Dissecting the loci of low-level quinine resistance in malaria parasites. Molecular Microbiology 52, 985–997. doi: 10.1111/j.1365-2958.2004.04035.x; MMI4035 [pii].CrossRefGoogle ScholarPubMed
Fidock, D. A., Nomura, T., Talley, A. K., Cooper, R. A., Dzekunov, S. M., Ferdig, M. T., Ursos, L. M., Sidhu, A. B., Naude, B., Deitsch, K. W., Su, X. Z., Wootton, J. C., Roepe, P. D. and Wellems, T. E. (2000). Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Molecular Cell 6, 861–871. doi: S1097-2765(05)00077-8 [pii].CrossRefGoogle Scholar
Fogh, S., Jepsen, S. and Effersoe, P. (1979). Chloroquine-resistant Plasmodium falciparum malaria in Kenya. Transactions of the Royal Society of Tropical Medicine and Hygiene 73, 228–229.CrossRefGoogle ScholarPubMed
Fojo, A., Akiyama, S., Gottesman, M. M. and Pastan, I. (1985). Reduced drug accumulation in multiply drug-resistant human KB carcinoma cell lines. Cancer Research 45, 3002–3007.Google ScholarPubMed
Foote, S. J., Galatis, D. and Cowman, A. F. (1990 a). Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proceedings of the National Academy of Sciences, USA 87, 3014–3017.CrossRefGoogle ScholarPubMed
Foote, S. J., Kyle, D. E., Martin, R. K., Oduola, A. M., Forsyth, K., Kemp, D. J. and Cowman, A. F. (1990 b). Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum. Nature 345, 255–258. doi: 10.1038/345255a0.CrossRefGoogle ScholarPubMed
Foote, S. J., Thompson, J. K., Cowman, A. F. and Kemp, D. J. (1989). Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of P. falciparum. Cell 57, 921–930. doi: 0092-8674(89)90330-9 [pii].CrossRefGoogle ScholarPubMed
Fry, M. and Pudney, M. (1992). Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4′-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochemical Pharmacology 43, 1545–1553.CrossRefGoogle Scholar
Geary, T. G., Jensen, J. B. and Ginsburg, H. (1986). Uptake of [3H]chloroquine by drug-sensitive and -resistant strains of the human malaria parasite Plasmodium falciparum. Biochemical Pharmacology 35, 3805–3812.CrossRefGoogle ScholarPubMed
Hartinuta, T., Migasen, S. and Boonag, D. (1962). Chloroquine resistance in Thailand. In UNESCO 1st Regional Symposium on Science Knowledge of Tropical Parasites, 5–9 November, 1962, pp. 143–153.Google Scholar
Hartwig, C. L., Rosenthal, A. S., D'Angelo, J., Griffin, C. E., Posner, G. H. and Cooper, R. A. (2009). Accumulation of artemisinin trioxane derivatives within neutral lipids of Plasmodium falciparum malaria parasites is endoperoxide-dependent. Biochemical Pharmacology 77, 322–336. doi: S0006-2952(08)00726-0 [pii]; doi: 10.1016/j.bcp.2008.10.015.CrossRefGoogle ScholarPubMed
Hastings, I. M. (2004). The origins of antimalarial drug resistance. Trends in Parasitology 20, 512–518. doi: S1471-4922(04)00212-0 [pii]; doi: 10.1016/j.pt.2004.08.006.CrossRefGoogle ScholarPubMed
Hastings, I. M. and Mackinnon, M. (1998). The emergence of drug-resistant malaria. Parasitology 117, 411–417.CrossRefGoogle ScholarPubMed
Henry, M., Briolant, S., Zettor, A., Pelleau, S., Baragatti, M., Baret, E., Mosnier, J., Amalvict, R., Fusai, T., Rogier, C. and Pradines, B. (2009). Plasmodium falciparum Na+/H+ exchanger 1 transporter is involved in reduced susceptibility to quinine. Antimicrobial Agents and Chemotherapy 53, 1926–1930. doi: AAC.01243-08 [pii]; doi: 10.1128/AAC.01243-08.CrossRefGoogle ScholarPubMed
Hudson, A. T., Dickins, M., Ginger, C. D., Gutteridge, W. E., Holdich, T., Hutchinson, D. B., Pudney, M., Randall, A. W. and Latter, V. S. (1991). 566C80: a potent broad spectrum anti-infective agent with activity against malaria and opportunistic infections in AIDS patients. Drugs under Experimental and Clinical Research 17, 427–435.Google ScholarPubMed
Hyde, J. E. (1989). Point mutations and pyrimethamine resistance in Plasmodium falciparum. Parasitology Today 5, 252–255. doi: 01694 75889 902573 [pii].CrossRefGoogle ScholarPubMed
Jarcho, S. and Torti, F. (1993). Quinine's Predecessor: Francesco Torti and the Early History of Cinchona. Johns Hopkins University Press, Baltimore, Maryland, USA.Google Scholar
Klonis, N., Crespo-Ortiz, M. P., Bottova, I., Abu-Bakar, N., Kenny, S., Rosenthal, P. J. and Tilley, L. (2011). Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion. Proceedings of the National Academy of Sciences, USA 108, 11405–11410. doi: 1104063108 [pii]; doi: 10.1073/pnas.1104063108.CrossRefGoogle ScholarPubMed
Knowles, G., Sanderson, A. and Walliker, D. (1981). Plasmodium yoelii: genetic analysis of crosses between two rodent malaria subspecies. Experimental Parasitology 52, 243–247.CrossRefGoogle ScholarPubMed
Korsinczky, M., Chen, N., Kotecka, B., Saul, A., Rieckmann, K. and Cheng, Q. (2000). Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrobial Agents Chemotherapy 44, 2100–2108.CrossRefGoogle Scholar
Krogstad, D. J., Gluzman, I. Y., Kyle, D. E., Oduola, A. M., Martin, S. K., Milhous, W. K. and Schlesinger, P. H. (1987). Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 238, 1283–1285.CrossRefGoogle ScholarPubMed
Kublin, J. G., Witzig, R. S., Shankar, A. H., Zurita, J. Q., Gilman, R. H., Guarda, J. A., Cortese, J. F. and Plowe, C. V. (1998). Molecular assays for surveillance of antifolate-resistant malaria. Lancet 351, 1629–1630. doi: S0140-6736(98)24022-0 [pii]; doi: 10.1016/S0140-6736(98)24022-0.CrossRefGoogle ScholarPubMed
Lim, P., Chy, S., Ariey, F., Incardona, S., Chim, P., Sem, R., Denis, M. B., Hewitt, S., Hoyer, S., Socheat, D., Merecreau-Puijalon, O. and Fandeur, T. (2003). pfcrt polymorphism and chloroquine resistance in Plasmodium falciparum strains isolated in Cambodia. Antimicrobial Agents and Chemotherapy 47, 87–94.CrossRefGoogle ScholarPubMed
Looareesuwan, S., Viravan, C., Webster, H. K., Kyle, D. E., Hutchinson, D. B. and Canfield, C. J. (1996). Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. American Journal of Tropical Medicine and Hygiene 54, 62–66.CrossRefGoogle ScholarPubMed
Martin, S. K., Oduola, A. M. and Milhous, W. K. (1987). Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 235, 899–901.CrossRefGoogle ScholarPubMed
Meshnick, S. R., Taylor, T. E. and Kamchonwongpaisan, S. (1996). Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiology Reviews 60, 301–315.CrossRefGoogle ScholarPubMed
Mungthin, M., Bray, P. G. and Ward, S. A. (1999). Phenotypic and genotypic characteristics of recently adapted isolates of Plasmodium falciparum from Thailand. American Journal of Tropical Medicine and Hygiene 60, 469–474.CrossRefGoogle ScholarPubMed
Nash, D., Nair, S., Mayxay, M., Newton, P. N., Guthmann, J. P., Nosten, F. and Anderson, T. J. (2005). Selection strength and hitchhiking around two anti-malarial resistance genes. Proceedings of the Royal Society B: Biological Science 272, 1153–1161. doi: GBBQXPNYG3WJ669D [pii]; doi: 10.1098/rspb.2004.3026.CrossRefGoogle ScholarPubMed
Nocht, B. and Werner, H. (1910). Beobachtungen uber eine relative Chininresistenz bei malaria aus Brasilien. Deutsche Medizinische Wochenschrift 36, 1557–1560.Google Scholar
Noedl, H., Se, Y., Schaecher, K., Smith, B. L., Socheat, D. and Fukuda, M. M. (2008). Evidence of artemisinin-resistant malaria in western Cambodia. New England Journal of Medicine 359, 2619–2620. doi: NEJMc0805011 [pii]; doi: 10.1056/NEJMc0805011.CrossRefGoogle ScholarPubMed
Nzila-Mounda, A., Mberu, E. K., Sibley, C. H., Plowe, C. V., Winstanley, P. A. and Watkins, W. M. (1998). Kenyan Plasmodium falciparum field isolates: correlation between pyrimethamine and chlorcycloguanil activity in vitro and point mutations in the dihydrofolate reductase domain. Antimicrobial Agents and Chemotherapy 42, 164–169.CrossRefGoogle ScholarPubMed
Okombo, J., Kiara, S. M., Rono, J., Mwai, L., Pole, L., Ohuma, E., Borrmann, S., Ochola, L. I. and Nzila, A. (2010). In vitro activities of quinine and other antimalarials and pfnhe polymorphisms in Plasmodium isolates from Kenya. Antimicrobial Agents and Chemotherapy 54, 3302–3307. doi: AAC.00325-10 [pii]; doi: 10.1128/AAC.00325-10.CrossRefGoogle ScholarPubMed
Olliaro, P. and Wells, T. N. (2009). The global portfolio of new antimalarial medicines under development. Clinical Pharmacology and Therapeutics 85, 584–595. doi: clpt200951 [pii]; doi: 10.1038/clpt.2009.51.CrossRefGoogle ScholarPubMed
Payne, D. (1988). Did medicated salt hasten the spread of chloroquine resistance in P. falciparum? Parasitology Today 4, 112–115.CrossRefGoogle Scholar
Peters, W. (1985). The problem of drug resistance in Malaria. Parasitology 90, 705–715.CrossRefGoogle ScholarPubMed
Peterson, D. S., Di Santi, S. M., Povoa, M., Calvosa, V. S., do Rosario, V. E. and Wellems, T. E. (1991). Prevalence of the dihydrofolate reductase Asn-108 mutation as the basis for pyrimethamine-resistant falciparum malaria in the Brazilian Amazon. American Journal of Tropical Medicine and Hygiene 45, 492–497.CrossRefGoogle ScholarPubMed
Peterson, D. S., Walliker, D. and Wellems, T. E. (1988). Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proceedings of the National Academy of Sciences, USA 85, 9114–9118.CrossRefGoogle ScholarPubMed
Pickard, A. L. and Wernsdorfer, W. H. (2002). Epidemiology of drug resistant malaria. Lancet Infectious Diseases 2, 209–218.Google Scholar
Plowe, C. V., Cortese, J. F., Djimde, A., Nwanyanwu, O. C., Watkins, W. M., Winstanley, P. A., Estrada-Franco, J. G., Mollinedo, R. E., Avila, J. C., Cespedes, J. L., Carter, D. and Doumbo, O. K. (1997). Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and resistance. Journal of Infectious Diseases 176, 1590–1596.CrossRefGoogle ScholarPubMed
Plowe, C. V., Kublin, J. G., Dzinjalamala, F. K., Kamwendo, D. S., Mukadam, R. A., Chimpeni, P., Molyneux, M. E. and Taylor, T. E. (2004). Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study. British Medical Journal 328, doi: 545-10.1136/bmj.37977.653750.EE; bmj.37977.653750.EE [pii].CrossRefGoogle ScholarPubMed
Povoa, M. M., Adagu, I. S., Oliveira, S. G., Machado, R. L., Miles, M. A. and Warhurst, D. C. (1998). Pfmdr1 Asn1042Asp and Asp1246Tyr polymorphisms, thought to be associated with chloroquine resistance, are present in chloroquine-resistant and -sensitive Brazilian field isolates of Plasmodium falciparum. Experimental Parasitology 88, 64–68. doi: S0014-4894(98)94195-9 [pii]; doi: 10.1006/expr.1998.4195.CrossRefGoogle ScholarPubMed
Price, R. N., Cassar, C., Brockman, A., Duraisingh, M., van, V. M., White, N. J., Nosten, F. and Krishna, S. (1999). The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand. Antimicrobial Agents and Chemotherapy 43, 2943–2949.CrossRefGoogle ScholarPubMed
Price, R. N., Nosten, F., Luxemburger, C., Ter Kuile, F. O., Paiphun, L., Chongsuphajaisiddhi, T. and White, N. J. (1996). Effects of artemisinin derivatives on malaria transmissibility. Lancet 347, 1654–1658.CrossRefGoogle ScholarPubMed
Radloff, P. D., Philipps, J., Nkeyi, M., Hutchinson, D. and Kremsner, P. G. (1996). Atovaquone and proguanil for Plasmodium falciparum malaria. Lancet 347, 1511–1514.CrossRefGoogle ScholarPubMed
Ranford-Cartwright, L. C. and Mwangi, J. M. (2012). Analysis of malaria parasite phenotypes using experimental genetic crosses of Plasmodium falciparum. International Journal for Parasitology 42, 529–534. doi: S0020-7519(12)00057-4 [pii]; doi: 10.1016/j.ijpara.2012.03.004.CrossRefGoogle ScholarPubMed
Roper, C., Pearce, R., Bredenkamp, B., Gumede, J., Drakeley, C., Mosha, F., Chandramohan, D. and Sharp, B. (2003). Antifolate antimalarial resistance in southeast Africa: a population-based analysis. Lancet 361, 1174–1181. doi: S0140-6736(03)12951-0 [pii]; doi: 10.1016/S0140-6736(03)12951-0.CrossRefGoogle Scholar
Saliba, K. J., Folb, P. I. and Smith, P. J. (1998). Role for the Plasmodium falciparum digestive vacuole in chloroquine resistance. Biochemical Pharmacology 56, 313–320. doi: S0006-2952(98)00140-3 [pii].CrossRefGoogle ScholarPubMed
Sanchez, C. P., Stein, W. and Lanzer, M. (2003). Trans stimulation provides evidence for a drug efflux carrier as the mechanism of chloroquine resistance in Plasmodium falciparum. Biochemistry 42, 9383–9394. doi: 10.1021/bi034269h.CrossRefGoogle Scholar
Schinkel, A. H. and Borst, P. (1991). Multidrug resistance mediated by P-glycoproteins. Seminars in Cancer Biology 2, 213–226.Google ScholarPubMed
Schmidt, K. F. (1995). Malaria research. Inbred parasites may spur resistance. Science 269, 1670.CrossRefGoogle ScholarPubMed
Schwobel, B., Alifrangis, M., Salanti, A. and Jelinek, T. (2003). Different mutation patterns of atovaquone resistance to Plasmodium falciparum in vitro and in vivo: rapid detection of codon 268 polymorphisms in the cytochrome b as potential in vivo resistance marker. Malaria Journal 2, 5.CrossRefGoogle ScholarPubMed
Sen, S. and Ferdig, M. T. (2003). Qtl analysis for drug discovery of genes involved in drug responses. Current Drug Targets – Infectious Disorders 3, 115–128.Google Scholar
Sidhu, A. B., Verdier-Pinard, D. and Fidock, D. A. (2002). Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298, 210–213. doi: 10.1126/science.1074045; 298/5591/210 [pii].CrossRefGoogle ScholarPubMed
Sirawaraporn, W. and Yuthavong, Y. (1984). Kinetic and molecular properties of dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant Plasmodium chabaudi. Molecular and Biochemical Parasitology 10, 355–367.CrossRefGoogle ScholarPubMed
Srivastava, I. K., Morrisey, J. M., Darrouzet, E., Daldal, F. and Vaidya, A. B. (1999). Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites. Molecular Microbiology 33, 704–711. doi: mmi1515 [pii].CrossRefGoogle ScholarPubMed
Su, X., Ferdig, M. T., Huang, Y., Huynh, C. Q., Liu, A., You, J., Wootton, J. C. and Wellems, T. E. (1999). A genetic map and recombination parameters of the human malaria parasite Plasmodium falciparum. Science 286, 1351–1353. doi: 7978 [pii].CrossRefGoogle ScholarPubMed
Su, X., Hayton, K. and Wellems, T. E. (2007). Genetic linkage and association analyses for trait mapping in Plasmodium falciparum. Nature Reviews Genetics 8, 497–506. doi: nrg2126 [pii]; 10.1038/nrg2126.CrossRefGoogle ScholarPubMed
Su, X., Kirkman, L. A., Fujioka, H. and Wellems, T. E. (1997). Complex polymorphisms in an approximately 330 kDa protein are linked to chloroquine-resistant P. falciparum in Southeast Asia and Africa. Cell 91, 593–603. doi: S0092-8674(00)80447-X [pii].CrossRefGoogle Scholar
Surrey, A. R. and Hammer, H. F. (1946). Some 7-substituted aminoquinoline derivatives. Journal of the American Chemical Society 68, 113–116. doi: 10.1021/ja01205a036.CrossRefGoogle ScholarPubMed
Sutherland, C. J., Laundy, M., Price, N., Burke, M., Fivelman, Q. L., Pasvol, G., Klein, J. L. and Chiodini, P. L. (2008). Mutations in the Plasmodium falciparum cytochrome b gene are associated with delayed parasite recrudescence in malaria patients treated with atovaquone-proguanil. Malaria Journal 7, 240-1475-2875-7-240 [pii]; doi: 10.1186/1475-2875-7-240.CrossRefGoogle ScholarPubMed
Urscher, M., Alisch, R. and Deponte, M. (2011). The glyoxalase system of malaria parasites – Implications for cell biology and general glyoxalase research. Seminars in Cell and Developmental Biology 22, 262–270. doi: 10.1016/j.semcdb.2011.02.003.CrossRefGoogle ScholarPubMed
Van Tyne, D., Park, D. J., Schaffner, S. F., Neafsey, D. E., Angelino, E., Cortese, J. F., Barnes, K. G., Rosen, D. M., Lukens, A. K., Daniels, R. F. et al. (2011). Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum. PLoS Genetics 7, doi: e1001383-10.1371/journal.pgen.1001383.CrossRefGoogle ScholarPubMed
Vijaykadga, S., Rojanawatsirivej, C., Cholpol, S., Phoungmanee, D., Nakavej, A. and Wongsrichanalai, C. (2006). In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003. Tropical Medicine and International Health 11, 211–219. doi: TMI1557 [pii]; doi: 10.1111/j.1365-3156.2005.01557.x.CrossRefGoogle ScholarPubMed
Walliker, D., Carter, R. and Sanderson, A. (1975). Genetic studies on Plasmodium chabaudi: recombination between enzyme markers. Parasitology 70, 19–24.CrossRefGoogle ScholarPubMed
Walliker, D., Sanderson, A., Yoeli, M. and Hargreaves, B. J. (1976). A genetic investigation of virulence in a rodent malaria parasite. Parasitology 72, 183–194.CrossRefGoogle Scholar
Wellems, T. E., Panton, L. J., Gluzman, I. Y., do Rosario, V. E., Gwadz, R. W., Walker-Jonah, A. and Krogstad, D. J. (1990). Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross. Nature 345, 253–255. doi: 10.1038/345253a0.CrossRefGoogle ScholarPubMed
Wellems, T. E. and Plowe, C. V. (2001). Chloroquine-resistant malaria. Journal of Infectious Diseases 184, 770–776. doi: JID010488 [pii]; doi: 10.1086/322858.CrossRefGoogle ScholarPubMed
Wellems, T. E., Walker-Jonah, A. and Panton, L. J. (1991). Genetic mapping of the chloroquine-resistance locus on Plasmodium falciparum chromosome 7. Proceedings of the National Academy of Sciences, USA 88, 3382–3386.CrossRefGoogle ScholarPubMed
Wells, T. N., Alonso, P. L. and Gutteridge, W. E. (2009). New medicines to improve control and contribute to the eradication of malaria. Nature Reviews Drug Discovery 8, 879–891. doi: nrd2972 [pii]; doi: 10.1038/nrd2972.CrossRefGoogle Scholar
Wernsdorfer, W. H. (1991). The development and spread of drug-resistant malaria. Parasitolology Today 7, 297–303. doi: 0169-4758(91)90262-M [pii].CrossRefGoogle ScholarPubMed
Wernsdorfer, W. H. and Payne, D. (1991). The dynamics of drug resistance in Plasmodium falciparum. Pharmacology and Therapeutics 50, 95–121.CrossRefGoogle ScholarPubMed
White, N. J. (1992). Antimalarial drug resistance: the pace quickens. Journal of Antimicrobial Chemotherapy 30, 571–585.CrossRefGoogle ScholarPubMed
White, N. J. (2004). Antimalarial drug resistance. Journal of Clinical Investigation 113, 1084–1092.CrossRefGoogle ScholarPubMed
Wichmann, O., Muehlberger, N., Jelinek, T., Alifrangis, M., Peyerl-Hoffmann, G., Muhlen, M., Grobusch, M. P., Gascon, J., Matteelli, A., Laferl, H., Bisoffi, Z., Ehrhardt, S., Cuadros, J., Hatz, C., Gjorup, I., McWhinney, P., Beran, J., da, C. S., Schulze, M., Kollaritsch, H., Kern, P., Fry, G. and Richter, J. (2004 a). Screening for mutations related to atovaquone/proguanil resistance in treatment failures and other imported isolates of Plasmodium falciparum in Europe. Journal of Infectious Diseases 190, 1541–1546. doi: JID32634 [pii]; doi: 10.1086/424469.CrossRefGoogle ScholarPubMed
Wichmann, O., Muehlen, M., Gruss, H., Mockenhaupt, F. P., Suttorp, N. and Jelinek, T. (2004 b). Malarone treatment failure not associated with previously described mutations in the cytochrome b gene. Malaria Journal 3, doi: 14-10.1186/1475-2875-3-14; 1475-2875-3-14 [pii].CrossRefGoogle Scholar
Wilson, C. M., Serrano, A. E., Wasley, A., Bogenschutz, M. P., Shankar, A. H. and Wirth, D. F. (1989). Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science 244, 1184–1186.CrossRefGoogle ScholarPubMed
Witkowski, B., Lelievre, J., Barragan, M. J., Laurent, V., Su, X. Z., Berry, A. and Benoit-Vical, F. (2010). Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. Antimicrobial Agents and Chemotherapy 54, 1872–1877. doi: AAC.01636-09 [pii]; doi: 10.1128/AAC.01636-09.CrossRefGoogle ScholarPubMed
Wongsrichanalai, C., Sirichaisinthop, J., Karwacki, J. J., Congpuong, K., Miller, R. S., Pang, L. and Thimasarn, K. (2001). Drug resistant malaria on the Thai-Myanmar and Thai-Cambodian borders. Southeast Asian Journal of Tropical Medicine and Public 32, 41–49.Google ScholarPubMed
Wootton, J. C., Feng, X., Ferdig, M. T., Cooper, R. A., Mu, J., Baruch, D. I., Magill, A. J. and Su, X. Z. (2002). Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418, 320–323. doi: 10.1038/nature00813; nature00813 [pii].CrossRefGoogle ScholarPubMed
World Health Organization (1961). Chemotherapy of Malaria. WHO Technical Report Series. WHO, Geneva.Google Scholar
World Health Organization (1973). Chemotherapy of Malaria and Resistance to Antimalarials. WHO, Geneva.Google Scholar
World Health Organization (1981). Drug-Resistant Malaria. World Health Organization, Geneva.Google Scholar
World Health Organization (1990). In vitro Microtest (Mark II) for the Assessment of Response of Plasmodium falciparum to Chloroquine, Mefloquine, Quinine, Sulfadoxine/Pyrimethamine and Amodiaquine. World Health Organisation, Geneva, Switzerland.Google Scholar
World Health Organization (2003). Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated Falciparum Malaria. World Health Organisation, Geneva, Switzerland.Google Scholar
World Health Organization (2010). Guidelines for the Treatment of Malaria. WHO, Geneva, Switzerland.Google Scholar