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MALCROSS


Malaria

Genetic Analysis of the Chloroquine Drug Resistance and the Accelerated-Resistance-to Multiple Drugs Phenotypes in the Human Malarial Parasite Plasmodium Falciparum
Framework programme:
5
Project number:
QLK2-CT-2002-00774
EC contribution:
€ 750 000
Duration:
36 months
Type:
RS
Starting date:
1 November 2002

Keywords: Malaria; chloroquine resistance; genetic cross; multi-drug resistance; genome scanning

Summary:

Chemotherapeutics against malaria now frequently fail in the field due to widespread resistance mechanisms. This project aims to do a genetic cross to identify genetic determinants of high-level chloroquine drug resistance and the accelerated-resistance-to-multiple-drugs (ARMD) phenotype. The study will provide new insight into the genetic basis of chloroquine resistance and the ARMD phenotype in Plasmodium. falciparum. A detailed knowledge of the molecular mechanisms underpinning chloroquine resistance and the ARMD phenotype may provide new opportunities for rational drug development.

Problem:

Physicians and medical support staff in many developing countries are engaged in a losing battle against malaria, an infectious disease that is endemic throughout most of Africa, Southeast Asia and Latin America, causing an estimated 300-500 million clinical cases and 1-3 million deaths annually. Options to control the spread of malaria are running out. Chloroquine, the first line antimalarial for more than thirty years, now frequently fails in the field due to widespread resistance. Alternative drugs that are as safe and affordable as chloroquine, and which could replace it as the mainstay antimalarial, are not yet available. Unfortunately, chloroquine is not the only drug compromised by resistance mechanisms. Parasite strains have emerged that are resistant to every common drug available, including chloroquine, quinine, mefloquine, pyrimethamine, cycloguanil and sulfadoxin. To make matters worse, these multi-drug resistant strains acquire resistances to new antimalarial compounds 1 000 times more frequently than do wild-type clones. This finding suggests that multi-drug resistant strains are predisposed to acquiring resistance to novel drugs, a phenotype called accelerated resistance to multiple drugs (ARMD). The mechanism responsible for the ARMD phenotype is not known, despite its important medical and public health implications. The ARMD phenotype, when not repressed, will inevitably undermine all future efforts to control malaria using intervention strategies based on chemotherapy. The mechanism underpinning chloroquine resistance is only partially understood, although a detailed understanding may provide new opportunities for therapeutic interventions. A genetic cross is proposed here to study both chloroquine resistance and the ARMD phenotype.

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