The mode of action and the mechanism of resistance to antimalarial drugs

Foote, Simon J.; Cowman, Alan F.

doi:10.1016/0001-706x(94)90061-2

Cited by 128 publications

(85 citation statements)

References 75 publications

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“…For the DHFR inhibitors the initial mutation conferring resistance is usually at position 108 (SER-ASN) in the gene encoding DHFR (Peterson et al 1988). This confers pyrimethamine resistance, but only slightly reduced sensitivity to cycloguanil (Foote & Cowman 1994;Foote et al 1990). Conversely, a serine to threonine mutation at position 108, plus an alanine to valine mutation at position 16 confers cycloguanil but not pyrimethamine resistance.…”

Section: (B) Me£oquine Resistancementioning

confidence: 99%

“…the drug concentrations are su¤cient to reduce the susceptible parasite population, but inhibit less or do not inhibit multiplication of the mutants (Peters 1990). Antimalarial drug resistance is usually a result either of changes in drug accumulation or e¥ux (chloroquine, amodiaquine, quinine, me£oquine, halofantrine resistance) or reduced a¤nity of the drug target resulting from point mutations in the respective genes encoding the target (pyrimethamine, cycloguanil, sulphonamide, atovoquone resistance) (Ward et al 1995;Foote & Cowman 1994). Other mechanisms of drug resistance found in bacteria such as transferable resistance genes, the production of drugdestroying enzymes, or the activation of accessory metabolic pathways, do not appear to be involved in antimalarial resistance.…”

Section: Introductionmentioning

confidence: 99%

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Antimalarial drug resistance and combination chemotherapy

White

1999

Phil. Trans. R. Soc. Lond. B

506

467

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Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration^e¡ect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly e¡ective combination partners because (i) they are very active antimalarials, producing up to 10 000-fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives.

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Section: (B) Me£oquine Resistancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antimalarial drug resistance and combination chemotherapy

White

1999

Phil. Trans. R. Soc. Lond. B

506

467

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“…ltpgpA is involved in low level oxyanion resistance, which includes resistance to antimony, the drug of choice in treatment of leishmaniasis (Callahan and Beverley, 1991), and ldmdrl is involved in resistance to several compounds included in the mammalian MDR spectrum (Hendrickson et al, 1993). In some resistant malaria parasites, Plasmodium falciparum, amplification of a Pglycoprotein gene (pfrmdrl) is observed (Foote and Cowman, 1994;Pussard and Verdier, 1994). For long it was thought that resistance to chloroquine, the drug of choice for treating malaria, was caused by a P-glycoprotein-mediated mechanism (Foote et al, 1989;Wilson et al, 1989).…”

mentioning

confidence: 99%

A P-glycoprotein protects Caenorhabditis elegans against natural toxins

Broeks¹,

Janssen²,

Calafat³

et al. 1995

Parasitology Today

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“…Ce gène, situé sur chromosome 4, code pour une enzyme intervenant dans la voie de synthèse des folates [50]. Elle est la cible des médicaments anti-folates (pyriméthamine, par exemple) qui, en inhibant son activité enzymatique, entraînent le blocage de la synthèse des pyrimidines et la réplication de l'ADN parasitaire [51].…”

Section: Approches Méthodologiquesunclassified