Gene's role in malaria drug resistance proved

In research supported by the National Institute of Allergy and Infectious Diseases (NIAID), David A. Fidock, Ph.D., has proved conclusively that the malaria-causing parasite Plasmodium falciparum became resistant to the anti-malarial drug chloroquine through mutations in a single parasite gene. Paradoxically, this gene acts as both a shield and a chink in the armor of P. falciparum by making the parasite less susceptible to chloroquine, but more susceptible to some other anti-malarials. Dr. Fidock and members of his laboratory at the Albert Einstein College of Medicine published their findings in this week's edition of the journal Science as part of a special issue that also includes publication of the genetic sequence of Anopheles gambiae, a mosquito that transmits malaria.

Chloroquine helped control or eliminate malaria throughout much of the world when it became widely used in the years following World War II. Chloroquine-resistant (CQR) P. falciparum emerged in Southeast Asia and South America in the 1950s and spread through much of Africa within two decades. Compared with chloroquine, drugs to treat CQR malaria are more expensive and cause more side effects while working less effectively. Resurgent malaria brings death and suffering to hundreds of millions and seriously impedes economic growth throughout malarious regions.

"Dr. Fidock's work provides direct and conclusive evidence of what was formerly only suspected; namely, that mutations in a single gene give P. falciparum the ability to resist chloroquine," says Michael Gottlieb, Ph.D., chief of NIAID's parasitology and international programs branch. "Curiously, the presence of this gene, named pfcrt, also appears to make P. falciparum more susceptible to two other anti-malarial drugs, artemisinin and quinine," he adds.

The gene finding has potentially important implications for malaria treatment and control, notes Dr. Gottlieb. "If we can develop further the methods we have of monitoring people for which variant of P. falciparum they are infected with, then health officials would be able to match whatever drugs work best against the most prevalent local or regional variant," he explains.

Dr. Fidock conducted earlier phases of this research as a member of NIAID's Laboratory of Malaria and Vector Research. The head of that lab, Thomas E. Wellems, M.D., Ph.D., contributed a "Viewpoint" article to the special issue of Science. In it, he writes, "Searches for new drugs to meet the need once filled by chloroquine require targets that are parasite-specific and can be hit with prompt and lethal effect." The sequencing of the P. falciparum genome gives scientists new ways to identify and attack the parasite's most vulnerable points, he notes.

NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

References: ABS Sidhu, D Verdier-Pinard and DA Fidock, Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 297: 210-13 (2002).

TE Wellems. Plasmodium chloroquine resistance and the search for a replacement antimalarial drug. Science 297: 124-26 (2002).

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institute of Allergy and Infectious Diseases is a component of the National Institutes of Health, U.S. Department of Health and Human Services

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