HANOVER, NH New biochemical studies may hold clues to more powerful malaria and pneumonia treatments that could save more than 2 million lives worldwide. Using baker's yeast as a surrogate disease model, researchers led by Dartmouth Medical School are exploring why enzymes in organisms that cause pneumonia and malaria are becoming increasingly resistant to antibiotics. This work could provide the answer to testing a new generation of drugs to combat these prevalent diseases.

Investigators used genetically modified yeast enzymes to pinpoint the mutations responsible for the antibiotic resistance of Pneumocystis jirovecii, which causes a type of pneumonia that is the most serious and prevalent AIDS-associated opportunistic infection and a threat to other immunocompromised patients, such as those undergoing therapy for cancer and organ transplantation. Pneumonia was responsible for more than 61,000 deaths in the US in 2001, according to the National Center for Health Statistics.

Appearing in the January 23 Journal of Biological Chemistry, the study examines the mutations responsible for disease's tolerance toward atovaquone (ATV), a drug prescribed since 1995 that inhibits a respiratory enzyme called the cytochrome bc1 complex, that is essential for the pathogen's survival. The lead author, Dr. Jacques Kessl, a research associate in biochemistry at DMS, said the study addresses recent evidence that indicates that pathogens that cause malaria and pneumonia are increasing resistance to ATV by developing mutations that prevent the drug from acting on the bc1 complex.

"We were able to isolate the genetic mutations that enable the pathogens to resist the drug when it is introduced to our yeast samples," said Dr. Bernard Trumpower, professor of biochemistry at DMS and corresponding author of the study. "As the genetically modified yeast strains now display atovaquone resistance identical to that found in pneumocystis, these yeast can be used
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Contact: Andy Nordhoff
DMS.Communications@Dartmouth.edu
603-650-1492
Dartmouth Medical School
20-Jan-2004

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