Researchers discover new antibiotic class

Columbus-Researchers have found that a promising new class of antibacterial chemicals inhibits one of the most fundamental processes of life; a cell's ability to express genetic material. Knowing exactly how these chemicals keep bacterial cells in check can help scientists make more effective antibiotics, researchers say.

Like many bacterial inhibitors, this new class of compoundsߣalled the CBR703 seriesߩnhibits RNA polymerase, the key enzyme in gene expression. However, the unique mechanism that these compounds use to inhibit RNA polymerase was previously unknown and is first described in the journal Science.

"It's a long way between knowing that something will kill bacteria and figuring out the exact process by which the bacteria is killed," says Dr. Irina Artsimovitch, a study co-author and an assistant professor of microbiology at The Ohio State University. "Other antibiotics also inhibit RNA polymerase, but the ones in this study use a radically different inhibitory mechanism."

According to the study, CBR703 inhibitors hindered the ability of RNA polymerase in E. coli to perform crucial catalytic functions, such as building molecules of RNA. Compounds in the CBR703 seriesß¡ll are synthetic chemicalsß²ender RNA polymerase useless by binding to a specific place on the enzymeß¡ necessary step in the process.

"Unless you know where the inhibitor binds, you can't draw any conclusions about how that inhibitor affects its target," Artsimovitch says. "On the other hand, once you have this information, you could predict if the inhibitor would be effective against a broad range of bacteria, as the binding site may not be the same in RNA polymerase enzymes from different bacteria."

She and her colleagues chose to study the effects of CBR703 inhibitors on E. coli, since the RNA polymerase enzyme in many pathogens is similar to that found in the E. coli bacteria. CBR703 compounds are not yet used as commercial antibiotics.

While the CBR703 inhibitors seemed to stop gene expression in E. coli, the researchers found that the compounds wouldn't inhibit RNA polymerase in human cells. Finding this lack of inhibition from human cells is key to designing new drugs, as some antibiotic compounds could harm both bacteria and human cells.

"When we find something that inhibits a particular process, it's easier to make targeted drugs," Artsimovitch says. "In this case, finding something that inhibited bacterial RNA polymerase lets us look at the structure of the enzyme and determine how to improve the inhibitors further to make them more effective."

Artsimovitch conducted the study with Robert Landick, a professor of microbiology at the University of Wisconsin-Madison and Clement Chu and A. Simon Lynch, both with Cumbre, Inc., a drug discovery firm in Dallas.

"Whenever a new class of antibacterial compounds becomes available, it leads to a surge in enthusiasm in the medical community, since novel antibiotics can provide new treatments, or at least may provide new weapons against pathogenic bacteria that have developed resistance to other drugs," Artsimovitch says.

This research was supported by grants from the National Institutes of Health and the USDA and in part by Cumbre, Inc.