A new strategy could improve the treatment of deadly infection – ScienceDaily

Researchers from the Washington University School of Medicine in St. Louis and Umea University in Sweden have discovered a compound that prevents and even reverses resistance to isoniazid, the most widely used antibiotic in the treatment of tuberculosis.

The research, published the week of May 6 in Proceedings of the National Academy of Sciences, was performed on bacteria developing in the laboratory, paving the way for future studies on animals and humans.

The use of the compound in combination with isoniazid could potentially restore the effectiveness of the antibiotic in people with drug-resistant tuberculosis. The compound could also enhance the antibiotic's power to kill TB bacteria – even those that are drug-sensitive – which means doctors could begin to consider reducing the currently prescribed six-month expensive treatment .

"It's very difficult for people to go on such a long diet," said Christina Stallings, senior author and PhD student, badociate professor of molecular microbiology at the Faculty of Medicine. "These are four drugs, they have side effects, it's not fun, the more antibiotics patients have to take, the more difficult it is to observe, and that can lead to drug resistance and Treatment Failure We have composed that sensitizes bacteria to an antibiotic, prevents drug resistance and even reverses it – at least in the lab – If we could turn this compound into a drug for humans, current treatments could be more effective and truly beneficial to fight this pandemic ".

Tuberculosis is caused by the bacteria Mycobacterium tuberculosis. Once inside the body, the bacteria turn into a harder form that can withstand more stress and is harder to kill. Rather than searching for new and better antibiotics, Stallings and his co-first authors, Kelly Flentie, a former postdoctoral researcher at Washington University, and Gregory Harrison, a graduate student, decided to look for compounds that prevent the bacteria from hardening. When placed in an oxygen-poor environment to mimic the stressful conditions of the tuberculosis bacteria inside the body, the bacteria congregate and form a thin film called a biofilm that is not only resistant to conditions of lack of oxygen, but also to antibiotics and other stressors.

With the help of Fredrik Almqvist, lead author and co-author, professor of chemistry at Umea University, they examined 91 compounds sharing a central chemical structure that inhibits biofilms in humans. other bacterial species. The researchers discovered a compound, called C10, that did not kill the TB bacteria, but prevented it from forming a biofilm.

Other experiments have shown that blocking biofilm formation with C10 facilitates the destruction of the bacterium with antibiotics and even prevents the development of antibiotic resistance. The researchers needed only a fraction of the amount of isoniazid to kill the tuberculosis bacteria when C10 was included, compared with isoniazid alone. In addition, one million TB bacteria become spontaneously resistant to isoniazid when cultured under typical laboratory conditions. But when the researchers developed the tuberculosis bacterium with isoniazid and the compound, the drug-resistant mutant bacterium never showed up.

"By combining C10, or something like that, with isoniazid, we could increase the potency of the antibiotic and prevent the bacteria from developing drug resistance," Stallings said. "This means we may be able to shorten the treatment regimen."

The most surprising is that the compound even reversed the drug resistance. Tuberculous bacteria with mutations in the katG gene can withstand treatment with isoniazid. But researchers have discovered that these bacteria die when they are treated with isoniazid and the compound. The bacterium had not lost its genetic resistance, but it had lost its ability to survive when it was exposed to isoniazid, provided that it was administered at the same time as C10.

"It was a totally unexpected discovery," Stallings said. "We did not know we would be able to reverse drug resistance, but that could mean that with all these millions of cases of isoniazid-resistant TB, if we use something like the C10, we could give people the opportunity to use isoniazid again. "

The compound is not ready for use in humans or even tested in animals, Stallings warned. This study was conducted on growing bacteria in a laboratory. Researchers are still determining if the compound is safe and how it could be treated by the body.

"We have this good compound and we have shown that it is possible to prevent and reverse antibiotic resistance," Stallings said. "But now we have to either improve the compound itself so that we can start testing it in animals, or find out how it prevents the formation of biofilm so that we can develop other drugs targeting the pathway. strategy to treat TB, but it will take time before it's a reality. "