Drug resistance in tuberculosis bacteria reversed in lab by research team in major breakthrough for future treatment

Researchers have found a compound that prevents and even reverses resistance to isoniazid, the most widely used antibiotic for treating TB

                            Drug resistance in tuberculosis bacteria reversed in lab by research team in major breakthrough for future treatment

Multi-drug-resistant (MDR) tuberculosis (TB) is a significant health problem globally. According to the World Health Organization (WHO), the bacteria that cause TB can develop resistance to the antimicrobial drugs used to cure the disease.

"Multi-drug-resistant TB is TB that does not respond to at least isoniazid and rifampicin, the two most powerful anti-TB drugs. In 2016, an estimated 490,000 people worldwide developed MDR-TB, and an additional 110,000 people with rifampicin-resistant TB were also newly eligible for MDR-TB treatment," says the WHO.

However, researchers from Washington University School of Medicine in St. Louis and Umea University in Sweden have discovered a compound (C10) that prevents and even reverses resistance to isoniazid - the most widely used antibiotic for treating tuberculosis.

"We had no idea we would be able to reverse drug resistance. But this could mean that with all those millions of isoniazid-resistant TB cases, if we use something like C10, we could give people the option of using isoniazid again," said co-senior author Christina Stallings, associate professor of molecular microbiology at the School of Medicine, in an official release by the Washington University School of Medicine.

The research, published in the Proceedings of the National Academy of Sciences journal, was conducted on bacteria grown in the lab and paves the way for further studies in animals and humans.

The findings are significant as they show that resistance to isoniazid is not absolute, and "there are vulnerabilities that can be exploited to extend the clinical relevance of this antibiotic".

This could help improve treatment strategies for TB in the future. 

"Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. As the deadliest pathogen in the world, Mtb causes infections responsible for 1.6 million deaths in 2017. The emergence of drug-resistant Mtb strains has exacerbated this already alarming epidemic. We have identified a small molecule, C10, that potentiates the activity of the frontline antibiotic isoniazid (INH) and prevents the selection for INH-resistant mutants. We find that C10 can even reverse INH resistance in Mtb. Therefore, our study reveals vulnerabilities that can be exploited to reverse INH resistance in Mycobacterium tuberculosis," says the research team in their findings.

The paper further says: "The unique ability of C10 to reverse INH resistance reveals that it may be possible to disarm INH resistance in the clinic, which would be of great utility to combat the global epidemic of drug-resistant TB. Future studies to identify the target of C10 and elucidate the mechanism by which C10 elicits these effects will uncover novel therapeutic targets that can be exploited for future drug development."

The research team, however, cautions that the compound is not ready to be used in people or tested on animals. The researchers are currently ascertaining whether the compound is safe and how it is likely to be processed by the body.

According to the university's news release, using the compound in conjunction with isoniazid could restore the antibiotic's effectiveness in people regarding drug-resistant tuberculosis.

The compound, says the research team, may also bolster the antibiotic's power to kill TB bacteria, even those sensitive to drugs, which implies that doctors could start thinking about cutting down the six-month treatment regimen prescribed currently.

"It is very hard for people to comply with such a long regimen. It's four drugs. They have side effects. It's no fun. 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. Here, we have found a compound that sensitizes bacteria to an antibiotic, prevents drug resistance from arising, and even reverses drug resistance, at least in the lab. If we can turn this compound into a drug for people, it could make our current therapies more effective and be beneficial for fighting this pandemic," Stallings says in the release.

According to a September 2018 Centers for Disease Control and Prevention (CDC) factsheet on the "costly burden of drug-resistant TB in the US", there is a significant human cost of those treated for drug-resistant TB, in which 9% die during treatment, 27% stop working, 73% are hospitalized, and 37% need home isolation.

Describing the experiment, the release says that instead of looking for new and better antibiotics, the research team decided to look for compounds that could 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. They 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," states the release.