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Chapter 30 : Drug-Resistant Falciparum Malaria: Mechanisms, Consequences, and Challenges

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Abstract:

Malaria is the major parasitic disease in tropical developing countries, causing approximately 300 to 500 million febrile illnesses and at least 1.2 million deaths each year. Current antimalarial drugs and mosquito control programs constitute important measures against malaria, but these have limitations that must be met by research to develop new drugs, vaccines, and insecticides. The spread of drug-resistant malaria is a major obstacle for malaria control. Allelic replacement studies have demonstrated that chloroquine-sensitive parasites can be converted to the resistant phenotype using DNA transfection methods that introduce codons for these mutations into the expressed sequences of the wild-type gene. Involvement of as one of these genes is supported by studies showing that substitutions of Lys with Ile or Asn at amino acid position 76 of the transporter change parasite responses to both chloroquine and quinine. Quantitative trait loci (QTL) analysis of a genetic cross between clones has distinguished the additive effects of multiple genes in quinine response, including , , and a third gene that is predicted to encode a sodium-hydrogen exchanger. Pyrimethamine and sulfadoxine are structurally similar to dihydrofolate and p-aminobenzoic acid (PABA), respectively, and act as competitive inhibitors of the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) enzymes of .

Citation: Hayton K, Fairhurst R, Naudé B, Su X, Wellems T. 2005. Drug-Resistant Falciparum Malaria: Mechanisms, Consequences, and Challenges, p 401-413. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch30

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Parasitic Diseases
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Antimalarial Drugs
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Dihydrofolate Reductase Inhibitors
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Malaria Life Cycle
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Figure 1

Changes in malaria death rates associated with the introduction of chloroquine and subsequent evolution of chloroquine-resistant malaria strains. (A) Malaria death rates in the 20th century. Dramatic reductions in mortality rates have been achieved outside sub-Saharan Africa. Mortality rates declined after the introduction of chloroquine but have risen again after the spread of chloroquine-resistant parasites across the continent. (Adapted from reference ). (B) Rise in mortality among children in the village of Mlomp, Senegal. Increased death rates associated with chloroquine resistance occurred chiefly among children <5 years old, the most susceptible age group in highly endemic areas. (Adapted from reference ).

Citation: Hayton K, Fairhurst R, Naudé B, Su X, Wellems T. 2005. Drug-Resistant Falciparum Malaria: Mechanisms, Consequences, and Challenges, p 401-413. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch30
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Figure 2

The malaria parasite life cycle (see text for descriptions).

Citation: Hayton K, Fairhurst R, Naudé B, Su X, Wellems T. 2005. Drug-Resistant Falciparum Malaria: Mechanisms, Consequences, and Challenges, p 401-413. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch30
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Figure 3

Spread of chloroquine-resistant from at least five independent origins under drug pressure.

Citation: Hayton K, Fairhurst R, Naudé B, Su X, Wellems T. 2005. Drug-Resistant Falciparum Malaria: Mechanisms, Consequences, and Challenges, p 401-413. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch30
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Figure 4

The decline of antimalarial efficacy in Thailand. (Adapted from references and ).

Citation: Hayton K, Fairhurst R, Naudé B, Su X, Wellems T. 2005. Drug-Resistant Falciparum Malaria: Mechanisms, Consequences, and Challenges, p 401-413. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch30
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