A growing rise in drug-resistant tuberculosis is a major obstacle to successfully treat the illness. Now, researchers at Washington University School of Medicine and Umeå University have found a molecular compound that prevents and even reverses resistance to the most widely used antibiotic for treating tuberculosis – isoniazid. The results of the study are published in the journal PNAS.
Text: Ingrid Söderbergh
The bacterium Mycobacterium tuberculosis causes turberculosis in humans.
PhotoNational Institute of Allergy and Infectious Diseases (NIAID)
The Swedish-American research team have discovered a molecule that in conjunction with isoniazid could potentially restore the antibiotic’s effectiveness in people with drug-resistant tuberculosis.
“The molecule may also bolster the antibiotic’s power to kill tuberculosis bacteria – even those sensitive to drugs. This could mean that doctors could start thinking about cutting down the onerous six-month treatment regimen they prescribe today,” says Fredrik Almqvist, Professor of chemistry at Umeå University, who took part in this pioneering study.
About 1.5 million people died of tuberculosis in 2017, which makes it the most lethal infectious disease worldwide. 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, researcher Christina Stallings, together with her fellow researchers at Washington University School of Medicine as well as Umeå researcher Fredrik Almqvist, decided to look for molecular compounds that could prevent bacteria from becoming resistant. When put in a low-oxygen environment to mimic the stressful conditions that tuberculosis bacteria encounter inside the body, the bacteria come together and form a thin biofilm. This biofilm is resilient to not only low-oxygen conditions but also to antibiotics and other stressors.
With the help of co-senior author Fredrik Almqvist and his research group, the researchers screened 91 molecular compounds that inhibits biofilms in other bacterial species. The molecular compounds were selected from a chemical database of compounds that share a core chemical structure. The researchers found one compound, called C10, that did not kill the tuberculosis 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 tuberculosis bacteria when C10 was included than with isoniazid alone. In addition, one out of a million tuberculosis bacteria spontaneously become resistant to isoniazid when grown under typical laboratory conditions. But when the researchers grew tuberculosis bacteria with isoniazid and the compound, the drug-resistant mutant bacteria never arose.
Most surprisingly, the compound even reversed drug resistance. Tuberculosis bacteria with mutations in a specific gene can withstand isoniazid treatment. But such bacteria die when treated with isoniazid plus the compound, the researchers discovered.
“These findings were totally unexpected. We had no idea we would be able to reverse drug resistance. But this could mean that by using a molecule like C10, we can give all those millions of people worldwide who carry isoniazid-resistant tuberculosis the option of using isoniazid again,” says Christina Stallings.
Although, the compound is not ready to be used in people or even be tested in animals, cautions Christina Stallings. 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. Now we’re working on improving the compound itself so we can start testing it in animals. We are also trying to figure out how it prevents biofilm formation so we can develop other drugs that target the pathway. In this work, Umeå researcher Christer Larsson and his co-workers also take part. We have found a new strategy to treat tuberculosis, but it’s going to take time before it’s a reality,” says Christina Stallings and Fredrik Almqvist.
Flentie K, Harrison G, Tükenmez H, Livny J, Good J, Sarkar S, Zhu D, Kinsella R, Weiss L, Solomon S, Schene M, Hansen M, Cairns A, Kulén M, Wixe T, Lindgren A, Chorell E, Bengtsson C, Krishnan K, Hultgren S, Larsson C, Almqvist F, Stallings CL. Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences. Week of May 6, 2019. DOI: 10.1073/pnas.1818009116.