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Chapter 23 : Mechanisms of Antimalarial Drug Action and Resistance

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Abstract:

This chapter talks about the modes of action and mechanisms of resistance to the antifolate drugs sulfadoxine-pyrimethamine (SP), pyrimethamine, and cycloguanil, as well as the quinoline-based drugs, notably chloroquine (CQ), mefloquine (MFQ), and quinine (QN). Antifolates comprise a group of drugs that work through inhibition of folate metabolism of various organisms, including malaria parasites. In all species, as well as other protozoa and some plants, dihydrofolate reductase (DHFR) exists as a bifunctional enzyme that includes thymidylate synthase (TS), which forms deoxythymidylate (dTMP) from deoxyuridylate, while another substrate, methylenetetrahydrofolate, is converted to dihydrofolate (DHF). Resistance to DHFR inhibitors, including pyrimethamine and cycloguanil, arose soon after their deployment as antimalarials. As an alternative to SP, a combination of dapsone with chlorcycloguanil, administered as its prodrug chlorproguanil, has recently been developed. Chloroquine use began worldwide in the late 1940s, and for several decades, this drug remained the gold standard in the prevention and treatment of uncomplicated malaria. Mechanistic models relating pH-dependent physiological changes in relation to CQ resistance (CQR) have recently seen intriguing yet contradictory developments. Direct evidence in support of a determining role for in CQR first came from transfection studies showing that coexpression of mutant in CQ-sensitive (CQS) parasites produced low-level, VP-reversible CQR. Focused and applied efforts from the academic, industrial, funding, and health care sectors on a significantly greater scale are vital to achieving any success in reducing the devastating impact that malaria maintains on the poorest nations of this world.

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
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Image of FIGURE 1
FIGURE 1

(A) Chemical reaction catalyzed by dihydrofolate reductase and structures of selected antimalarial DHFR inhibitors. The prodrug proguanil is converted into the DHFR inhibitor cycloguanil. (B) Chemical reaction catalyzed by dihydropteroate synthase, together with the structures of the DHPS inhibitors sulfadoxine and dapsone.

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
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Image of FIGURE 2
FIGURE 2

De novo synthesis, salvage, and utilization of folate cofactors in malaria parasites. Most enzymes in the de novo synthesis pathway in the genome have been identified, with the exception of dihydroneopterin aldolase. The salvage pathways have been investigated mainly through metabolic labeling analyses.

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
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Image of FIGURE 3
FIGURE 3

Possible evolution of antifolate resistance through cumulative mutations. The first mutation is considered to be S108N, followed by other mutations that confer increasing levels of resistance. The quadruple mutant N51I+C59R+S108N+I164L, resistant to both pyrimethamine and cycloguanil, is found in southeast Asia, while C50R+N51I+S108N+I164L might be present at very low levels in Africa. Another mutant, A16V+S108T, is resistant only to cycloguanil and not pyrimethamine.

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
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Image of FIGURE 4
FIGURE 4

Chemical structures of major antimalarial quionolines, as well as the endoperoxide-containing drug artemisinin.

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
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Image of FIGURE 5
FIGURE 5

PfCRT predicted structure. PfCRT has been postulated to possess 10 transmembrane helices, with the N and C termini extending into the parasite cytoplasm. Filled circles indicate the positions of mutations published from full-length cDNA sequences identified in CQ-resistant parasites from field samples, as well as additional mutations identified in amantadine- and halofantrine-resistant parasites selected in vitro ( Table 1 ). (Reprinted from [ ] with permission from the publisher.)

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
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Image of FIGURE 6a
FIGURE 6a

Cumulative percentage of patients free from malaria after treatment with MFQ monotherapy (A) or MFQ and 3 days of artesunate (B). Open circles, 1 copy; triangles, 2 copies; diamonds, 3+ copies. (Reprinted from The Lancet [ ] with permission from the publisher.)

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
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Image of FIGURE 6b
FIGURE 6b

Cumulative percentage of patients free from malaria after treatment with MFQ monotherapy (A) or MFQ and 3 days of artesunate (B). Open circles, 1 copy; triangles, 2 copies; diamonds, 3+ copies. (Reprinted from The Lancet [ ] with permission from the publisher.)

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23
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Tables

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TABLE 1

allelic variants identified in field isolates and laboratory-adapted lines

Citation: Uhlemann A, Yuthavong Y, Fidock D. 2005. Mechanisms of Antimalarial Drug Action and Resistance, p 429-461. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch23

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