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Yeast aids development of medicines

Published February 9, 2004; Category: DARTMOUTH MEDICAL SCHOOL

Antibiotic resistance makes malaria and pneumonia tougher
Bernard Trumpower, Benjamin Lange and Jacques Kessl
Bernard Trumpower, Benjamin Lange and Jacques Kessl, researchers at DMS whose studies on yeast shed light on the genetic mutations responsible for antibiotic resistance in malaria and pneumonia pathogens. (photo by Andrew Nordhoff)

New biochemical studies may hold clues to more powerful malaria and pneumonia treatments that could save 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 diseases. Malaria and pneumonia are responsible for more than 2 million deaths worldwide a year, said Bernard Trumpower, Professor of Biochemistry, who headed the study.

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 immuno-compromised patients, like those undergoing therapy for cancer and organ transplantation.

Appearing in the Jan. 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, Jacques Kessl, Research Associate in Biochemistry, 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," Trumpower said. "As the genetically modified yeast strains now display atovaquone resistance identical to that found in pneumocystis, these yeasts can be used to design new drugs to make the appearance of resistance more unlikely."

The study builds on prior research in Trumpower's lab that used yeast enzymes as accurate and easily modified models to explore the resistance to ATV. It is not possible to grow pneumocystis enzymes in the large quantities necessary to isolate and study the cytochrome bc1 complex. Yeast is an excellent resource that can be manufactured in large quantities and can be easily modified to take on the qualities of more dangerous pathogens.

The researchers were able to genetically transfer into the yeast cytochrome b mutations like those found in the atovaquone-resistant pneumocystis and found that these mutations caused the yeast to acquire similar resistance to ATV.

The team used a computer program to construct molecular models of the enzymes.

"We can now visualize the different mutations in three dimensions to predict how the enzyme will react to different changes, like the introduction of a new antibiotic," said co-author Benjamin Lange, Research Technician in Biochemistry.

The co-authors of the study are Steven Meshnick from the University of North Carolina and Brigitte Meunier from the Wolfson Institute for Biomedical Research in London. The study was funded in part by the National Institutes of Health.

By ANDREW NORDHOFF

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Last Updated: 12/17/08