Keywords: Malaria; chloroquine resistance; genetic cross; multi-drug resistance; genome scanning
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.
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.
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.
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.
The results may provide new insight into drug targets. As such, the project may be of interest to the pharmaceutical industry.
Hygiene-Institut, Abt. Parasitologie
Im Neuenheimer Feld 324
Tel: +49 6221 567845
Fax: +49 6221 564643
Hermann Funk (authorised person)
Tel: +49 6221 567080
Fax: +49 6221 565925
|Official Address||Other Information|
|2||Alan Thomas||Foundation Biomedical Primate Research Center (BPRC) |
Lange Kleiweg 139
NL-2280 GH Rijswijk
|Tel: +31 15 284 2538 |
Fax: +31 15 284 3986
|3||Dominique Mazier||Institut National de la Santé et de la Recherche Médicale |
184 Rue du Faubourg St-Antoine
|Tel: +33 1 40 77 97 37 |
Fax: +33 1 45 83 88 58
|4||Robert Sauerwein||Stichting Katholieke Universiteit |
Geert Grooteplein 10
NL-6500 HB Nijmegen
|Tel: +31 24 361 4306 |
Fax: +31 24 354 0216
|5||Socrates Herrera||Fundacion Centro de Primates |
Instituto de Inmunologia
Calle 4B # 36
|Tel: +57 2 558 3937 |
Fax: +57 2 557 0449