Researchers at Washington University School of Medicine in St. Louis and Umea University in Sweden have found a compound that prevents and even reverses resistance to isoniazid, the most widely used antibiotic for treating tuberculosis, a disease that killed 1.5 million people in 2017.
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.
With the help of co-senior author Fredrik Almqvist, PhD, a professor of chemistry at Umea University, 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. 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 1 million TB bacteria spontaneously become resistant to isoniazid when grown under typical laboratory conditions. But when the researchers grew TB bacteria with isoniazid and the compound, the drug-resistant mutant bacteria never arose.
Most surprisingly, the compound even reversed drug resistance. TB bacteria with mutations in the gene katG can withstand isoniazid treatment. But such bacteria die when treated with isoniazid plus the compound, the researchers discovered. The bacteria had not lost their genetic resistance; they’d lost the ability to survive when exposed to isoniazid, as long as it was given alongside C10.
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.
“We have this great compound, and we’ve shown that it’s possible to prevent and reverse antibiotic resistance,” Stallings said. “But now we have to either improve on the compound itself so we can start testing it in animals, or figure out how it prevents biofilm formation so we can develop other drugs that target the pathway. We have a new strategy to treat TB, but it’s going to take time before it’s a reality.”
This story was edited for length and style using materials from the Washington School of Medicine in St. Louis.