New Class of Antibiotics on the Horizon

Author(s):

A team of researchers has discovered what could become a new and more effective kind of antibiotic that disrupts protein synthesis in bacteria and makes them unable to replicate.

This article published with permission from The Burrill Report.

A team of researchers has discovered what could become a new and more effective kind of antibiotic that disrupts protein synthesis in bacteria and makes them unable to replicate. With drug-resistant bacterial infections on the rise, it could be a solution to a major health concern around the world.

The researchers, led by Kenneth Keiler, associate professor of biochemistry and molecular biology at Penn State University, have found that an early step in the protein synthesis process unique to bacteria is a previously unrecognized drug target.

Back in 1996 when he was a graduate student, Keiler discovered something now called the trans-translation process. Since then he has focused on finding molecules to disrupt this step in bacterial protein synthesis.

“The idea is to throw a wrench into the protein-synthesis assembly line and prevent bacterial organisms from making copies of themselves,” says Keiler.

Trans-translation is a quality-control mechanism found in all species of bacteria that helps to keep the bacterium’s assembly line production of proteins moving.

“Faulty messenger RNA — which conveys genetic information from DNA to proteins — can block the bacterium’s synthesis machinery,” says Keiler. “The trans-translation mechanism removes these blockages from the assembly line, thereby keeping the bacterium’s system running smoothly” he says.

Interfering with this mechanism wreaks havoc on protein synthesis quality control and bacteria are not able to generate the correct proteins they need to survive.

Keiler and his Penn State research team performed high-throughput screening on a library of 663,000 molecules to find 46 that disrupted the quality control process in a common E. Coli bacteria strain. They then tested the most promising candidate and found it was 100 times more effective at inhibiting growth of the bacteria that cause tuberculosis than currently used antibiotics. The compound was also able to inhibit the growth of distantly related bacteria, suggesting it has potential to be a broad spectrum antibiotic.

The class of antibiotic currently on the market that inhibits a different step in protein synthesis and targets the bacterial ribosome includes the drugs tetracycline and streptomycin. Most resistance to this class of drug likely evolved from bacteria’s ability to mutate one of their own housekeeping enzymes. Since the trans-translation quality control mechanism involves multiple proteins, resistance will be more difficult to develop.

“Resistant mutants probably could evolve eventually, but at least it looks like it will be very difficult

,” says Keiler

. "That means resistant mutants might be slow to arise and spread."