Skip to main content
Premium Trial:

Request an Annual Quote

Targeting a Pathway to Kill Tuberculosis

Premium

There's a new way to strike at the tuberculosis bacterium, says Albert Einstein College of Medicine's William Jacobs. By knocking out an enzyme essential to the bacterium's ability to metabolize carbohydrates, Jacobs and his colleagues were able to kill it. "The discovery was somewhat serendipitous," Jacobs says.

It began when the team of researchers set out to find why some tuberculosis bacteria persist in patients despite treatment, and what the bacteria eat during the persistent state. The researchers started by trying to find the bacteria's carbon source, and after knocking out its storage lipids and not seeing any effect on the bug, they went back and found that tuberculosis uses glucan as an energy storing compound. Enzymologists Karl Syson and Stephen Bornemann of the John Innes Center in Norwich, UK, collaborated with Jacobs and his team and found that two enzymes, TreS and Pep2, work together to transform the sugar trehalose into a maltose 1-phosphate intermediary. The GlgE enzyme, another essential component in the tuberculosis metabolic pathway, then converts that into glucan to power the bacterium. Jacobs says this is the first time researchers have discovered this metabolic pathway.

Working with Mycobacteria smegmatis, a close relation of M. tuberculosis, the researchers then tried knocking out every Glg-like gene, and found when the bacteria didn't have GlgE, the excess maltose 1-phosphate acted as a poison and killed the bacteria. "We were absolutely amazed we could knock the whole gene out because it's essential to the survival of smegmatis, but we made the deletion," Jacobs says. "We basically caused a metabolic disease which leads to the death of the bug."

The researchers also looked into whether knocking out the TreS pathway would have the same effect — but found that simply eliminating TreS itself wouldn't kill the bacteria, as it would just find another way to make the glucan it needs. GlgE inhibitors show the most promise for finding new treatments for tuberculosis, according to Jacobs. In just four days, he says, the researchers saw that 99 percent of the bacteria were dead. "This kills as well as our best TB drugs. When we inactivate this target, we kill as well as isoniazid or rimfampicin," he says. Though there are treatments for tuberculosis, the bacteria have evolved to get around the drugs.

Humans, however, have no homolog for GlgE, nor do the gut bacteria that humans rely on for digestion. A GlgE inhibitor wouldn't have any adverse effects, making it an attractive drug target. Jacobs and his team are continuing the work and are developing a high-throughput screen to actively search for a GlgE inhibitor. "I think we could have inhibitors within the next year," he says. "Maybe even in the next six months."

The Scan

J&J Booster Support

A US Food and Drug Administration advisory panel has voted to support a booster dose of Johnson & Johnson's SARS-CoV-2 vaccine, according to the Los Angeles Times.

To Keep the Cases Moving

The president of the UK Royal College of Pathologists tells the Financial Times that more investment is needed to tackle a backlog of cases.

NAS Expels Archaeologist

Science reports Luis Jaime Castillo Butters' expulsion is the first of an international member from the US National Academy of Sciences.

PLOS Papers on Angelman Syndrome-Like Cases, Salmonella Paratyphi A, SARS-CoV-2 in Brazil

In PLOS this week: exome sequencing analysis of Angelman syndrome-like cases, genetic epidemiology of Salmonella Paratyphi A, and more.