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

Aim:

The aim of the project is to identify candidate genes mediating chloroquine drug resistance and the ARMD phenotype in the human malarial parasite P. falciparum.

Expected results:

The project expects to identify genes that are altered in malarial parasites revealing chloroquine resistance and the ARMD phenotype. This will provide a better understanding of the molecular mechanisms underpinning these two pathogenic phenotypes, which in turn, may open up new opportunities for drug intervention.

Potential applications:

The results may provide new insight into drug targets. As such, the project may be of interest to the pharmaceutical industry.

Coordinator:

Michael Lanzer
Universitätsklinikum Heidelberg
Hygiene-Institut, Abt. Parasitologie
Im Neuenheimer Feld 324
69120 Heidelberg
Germany
Tel: +49 6221 567845
Fax: +49 6221 564643
E-mail: michael_lanzer@med.uni-heidelberg.de

Hermann Funk (authorised person)
Tel: +49 6221 567080
Fax: +49 6221 565925
E-mail: Hermann_Funk@med.uni-heidelberg.de

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Alan ThomasFoundation Biomedical Primate Research Center (BPRC)
Lange Kleiweg 139
NL-2280 GH Rijswijk
The Netherlands
Tel: +31 15 284 2538
Fax: +31 15 284 3986
E-mail: thomas@bprc.nl
3Dominique MazierInstitut National de la Santé et de la Recherche Médicale
184 Rue du Faubourg St-Antoine
Hôpital St-Antoine
FR-75571 Paris
France
Tel: +33 1 40 77 97 37
Fax: +33 1 45 83 88 58
E-mail: mazier@ext.jussieu.fr
4Robert SauerweinStichting Katholieke Universiteit
Geert Grooteplein 10
NL-6500 HB Nijmegen
The Netherlands
Tel: +31 24 361 4306
Fax: +31 24 354 0216
E-mail: r.sauerwein@mmb.azn.nl
5Socrates HerreraFundacion Centro de Primates
Instituto de Inmunologia
Calle 4B # 36
Cali
Colombia
Tel: +57 2 558 3937
Fax: +57 2 557 0449
E-mail: sherrera@inmuno.org

 
 
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