Drug-resistant Tuberculosis Reversed in Lab as Scientists Look to Restore Antibiotic's Effectiveness

Washington: Scientists have found a compound that prevents and even reverses resistance to a widely used antibiotic for treating tuberculosis -- the most lethal infectious disease worldwide.

A growing rise in drug-resistant tuberculosis (TB) is a major obstacle to successfully treating the illness. About 1.5 million people died of TB in 2017, making it the most deadly infectious disease in the world.

Researchers at Washington University in the US and Umea University in Sweden reversed resistance to isoniazid, the most widely used antibiotic for treating TB.

The research, published in the journal Proceedings of the National Academy of Sciences, was conducted in bacteria growing in the lab, setting the stage for future studies in animals and people.

Using the compound in conjunction with isoniazid potentially could restore the antibiotic's effectiveness in people with drug-resistant tuberculosis.

The compound also may bolster the antibiotic's power to kill TB bacteria -- even those sensitive to drugs -- which means doctors could start thinking about cutting down the onerous six-month treatment regimen they prescribe today.

"It is very hard for people to comply with such a long regimen. It's four drugs. They have side effects," said Christina Stallings, an associate professor at the Washington University.

"The longer people have to be on antibiotics, the more issues with patient compliance you get, and that can lead to drug resistance and treatment failure," said Stallings.

"Here, we've found a compound that sensitizes bacteria to an antibiotic, prevents drug resistance from arising, and even reverses drug resistance -- at least in the lab," she said.

"If we can turn this compound into a drug for people, it could make our current therapies more effective and be really beneficial for fighting this pandemic," she said.

Tuberculosis is caused by the bacterium Mycobacterium tuberculosis. Once inside the body, the bacteria morph into a tougher form that can withstand more stress and is harder to kill.

Rather than look for new and better antibiotics, the researchers decided to look for compounds that prevent the bacteria from toughening up.

When put in a low-oxygen environment to mimic the stressful conditions TB bacteria encounter inside the body, the bacteria come together and form a thin film called a biofilm that is resilient to not only low-oxygen conditions but also to antibiotics and other stressors.

The team screened 91 compounds that share a core chemical structure that inhibits biofilms in other bacterial species.

The researchers found one compound, called C10, that did not kill the TB bacteria but prevented them from forming a biofilm.

Further experiments showed that blocking biofilm formation with C10 made the bacteria easier to kill with antibiotics and even curbed the development of antibiotic resistance.

The researchers needed only a fraction of the amount of isoniazid to kill the TB bacteria when C10 was included than with isoniazid alone.

In addition, one out of one million TB bacteria spontaneously become resistant to isoniazid when grown under typical laboratory conditions.

However, when the researchers grew TB bacteria with isoniazid and the compound, the drug-resistant mutant bacteria never arose.

"By combining C10, or something like it, with isoniazid we could enhance the potency of the antibiotic and block the TB bacteria from developing drug resistance," Stallings said.

"That means we might be able to shorten the treatment regimen," she said.

The compound is not ready to be used in people or even tested in animals, Stallings cautioned.

This study was conducted on bacteria growing in a lab. The researchers are still figuring out whether the compound is safe and how it might be processed by the body.