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OHSU Researchers Reveal Cellular-Level Systems Behind Drug Resistance

   Portland, Ore.

Research may help result in design of "smarter drugs" including antibiotics to combat bacteria, cancer

Researchers at Oregon Health & Science University have provided the first visual insight into one of the defense mechanisms that bacteria and other disease-related cells, such as cancer cells, utilize to develop resistance to various drugs, including antibiotics. These defense systems have the ability to limit or prevent drug effectiveness. This research could lead to the design of "smarter drugs" to interfere with or overwhelm this defense mechanism, allowing drugs to reach their target. The research was conducted by Richard Brennan, Ph.D., a professor of biochemistry and molecular biology in OHSU's School of Medicine, in collaboration with Maria Schumacher, Ph.D., a Burroughs Wellcome Career Development Awardee; Marshall Miller, a technician in the Brennan lab; and colleagues at the University of Sydney, Australia. Their results will be published in the Dec. 7, edition of the journal Science.

"Recently, there have been plenty of concerns and discussions about antibiotic drug resistance. We hope that in a small way, this work will help provide a solution," said Brennan.

This research was conducted on a protein from the bacterium Staphylococcus aureus, a human pathogen. Staphylococci can invade or attack any part of the human body. The infections caused by these cells can result in a variety of health problems ranging from minor skin infections to joint problems to pneumonia to death.

Scientists at OHSU knew that a protein called QacA, which is found in the membrane of the staphylococcus cell, acts like a pump, removing various substances including drugs that may be harmful to the cell. A second line of defense for these cells is a related protein called QacR, which is located in the cell interior. When drugs and other substances are able to bypass the pumps and enter the cell, these proteins recognize the intruders, bind with them and direct the cell to produce additional QacA proteins to pump away the drug.

"A key finding of this research lies in the physical makeup of the QacR protein. Previously, scientists had difficulty understanding how one protein could bind to a variety of drugs, each drug having its own unique chemical structure," said Brennan. "This research gave us three-dimensional pictures of QacR bound to different drugs and thereby allowed us to visualize how QacR is built to bind to a wide variety of compounds in a variety of locations on the protein."

Scientists at OHSU hope this work will ultimately result in structure-based drug design because Brennan and Schumacher believe that the mechanisms that QacR and QacA use to bind to drugs is similar. Using this new structural information, researchers will try to disable the multidrug pumps, thus allowing existing or new drugs to kill the offending bacteria. In addition to providing new information on staphylococcus drug resistance, OHSU researchers believe their structures will provide insight into the mechanisms of multidrug drug resistance of other bacteria and tumor cells.

"One approach to kill these pathogenic bacteria is to shutdown multidrug efflux by clogging or dramatically slowing down the QacA pumps on the surface of the cell. This might allow drugs the necessary amount of time to do their job," explained Brennan. "Another possibility is to develop drugs that will cause an overproduction of the QacA protein, which by itself might be lethal to the bacterium."

This research was funded by the National Institute of Allergy and Infectious Diseases, a component of the National Institutes of Health. The Burroughs Wellcome Trust provided additional funding.

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