October 22, 2008

• Bacterial binding site for antibiotic found

• Enzyme that transmits DNA targeted

• New targets for drug design

BIRMINGHAM, Ala. - UAB (University of Alabama at Birmingham) researchers have discovered how one highly effective antibiotic finds and destroys its targeted bacteria. The findings could have great implications for combating antibiotic resistance and promoting antibiotic efficiency. In research published online Oct. 22 in Nature, the UAB team pinpointed the place on bacteria where an antibiotic called myxopyronin launches its attack, and why that attack is successful.

Dmitry Vassylyev, Ph.D., professor of biochemistry and molecular genetics, and colleagues found that myxopyronin binds to and inhibits a crucial bacterial enzyme, RNA polymerase. All living organisms use RNA polymerase to transfer genetic instructions stored in DNA to messenger RNA, which in turn transfer those instructions to ribosomes. Ribosomes are factories producing proteins that carry out all processes required for cells to live. If RNA polymerase is not functioning properly, the factories shut down.

When myxopyronin binds to RNA polymerase, it changes the structure of a segment called the switch-2 segment of the enzyme, inhibiting its function of reading and transmitting the DNA code. This prevents RNA polymerase from delivering genetic information to the ribosomes, causing the bacteria to die.

"Prior to this work, we knew myxopyronin killed bacteria, but we did not know the precise way it accomplished this task," Vassylyev said. "Now we know it binds with RNA polymerase at a specific segment and by doing so, it prevents the bacteria from reproducing. This tells us a great deal about how the antibiotic works, but tells us even more about the workings of RNA polymerase."

And that could lead to new strategies for drug design to overcome antibiotic resistance, a growing concern in medicine as many bacteria have become resistant to the drugs commonly used to kill them. Bacteria are living organisms whose primary function is to reproduce and spread. If a drug interferes with that process, genetic changes can occur in the bacteria enabling it to side-step the drug and survive.

"These studies help show how bacterial RNA polymerase works," said Tim Townes, Ph.D., professor and chair of UAB's Department of Biochemistry and Molecular Genetics. "The more we know of what these enzymes do at each stage of the process, the better we can design new drugs that will interfere with that process, or improve existing drugs to overcome the growing resistance."

This research was funded through grants from the National Institutes of Health. Vassylyev collaborated with researchers at Ohio State University, New York University and Anadys Pharmaceuticals.