New Class Of Antibiotics Stops Pathogens In Their Genetic Tracks

Like many bacterial inhibitors, this new class of compounds – called the CBR703 series – inhibits 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 this week's 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," said Irina Artsimovitch, a study co-author and an assistant professor of microbiology at 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 Escherichia coli to perform crucial catalytic functions, such as building molecules of RNA. Compounds in the CBR703 series – all are synthetic chemicals – render RNA polymerase useless by binding to a specific place on the enzyme – a 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 said. "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 said. "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.

The researchers at Cumbre, Inc., prepared and analyzed a large set of chemical compounds in order to find one that would inhibit transcription in E. coli. Transcription is the first step of gene expression, when a copy of RNA is made from a DNA sequence.

After finding that CBR703 inhibited transcription in E. coli, the researchers ran the bacteria through a series of tests that allowed them to see where and when during transcription the inhibitor acted on the enzyme.

Transcription is a multi-step process in which the genetic information from DNA is transcribed, or written on, RNA. Transcription is key for all cellular processes. In this study, CBR703 inhibited the addition of nucleotides – individual units that make up an RNA molecule – thus keeping a new strand of RNA from forming.

"Knowing how a new antibiotic acts on its target takes the process of making new drugs to a new level, allowing for better understanding of a drug's direct- and side-effects," she said. This new series of antibacterial compounds holds great promise for designing drugs specifically targeted to major classes of bacterial pathogens, such as those that cause pneumonia and tuberculosis.

"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 said.

This research was supported by grants from the National Institutes of Health and the U.S. Department of Agriculture and in part by Cumbre, Inc. Artsimovitch has no link to Cumbre beyond the scope of this study.