Treating tuberculosis when antibiotics no longer work

Researchers have identified new antibiotic molecules that target Mycobacterium tuberculosis and make it less pathogenic for humans. In addition, some of the discovered substances could make it possible to renew the treatment of tuberculosis with available drugs, including strains of the bacteria that have already developed drug resistance.

The research is published in an article titled “Discovery of dual-activity ethionamide boosters inhibiting the secretion system of Mycobacterium tuberculosis ESX-1” in Cellular chemical biology.

Tuberculosis (TB) – or “consumption,” as it was once called – primarily affects the lungs, but can also damage other organs. If diagnosed early and treated with antibiotics, it is curable. Although the disease is relatively rare in most Western European countries, it is still among the world’s deadliest infectious diseases.

According to the World Health Organization (WHO), only COVID-19 was more deadly than tuberculosis in 2022. The disease also caused almost twice as many deaths as HIV/AIDS. More than 10 million people continue to contract tuberculosis each year. This is mainly due to insufficient access to medical care in many countries.

Limited targets

Multidrug-resistant tuberculosis appears particularly in Eastern Europe and Asia. This is of particular concern to researchers because, like all bacteria that infect humans, Mycobacterium tuberculosis has only a limited number of targets for conventional antibiotics. This makes it increasingly difficult to discover new antibiotic substances in research laboratories.

Together with colleagues at the Pasteur Institute in Lille, France, and the German Center for Infection Research (DZIF), researchers at Cologne University Hospital have now identified an alternative treatment strategy for the bacteria. The team used high-throughput host cell-based methods to test the molecules’ ability to stem the multiplication of bacteria in human immune cells: out of a total of 10,000 molecules, this procedure allowed them to isolate some a handful whose properties they scrutinized more closely. during the study.

Double attack

Ultimately, researchers identified virulence blockers that use target structures fundamentally distinct from those targeted by conventional antibiotics.

“These molecules probably lead to significantly less selective pressure on the bacteria, and thus less resistance,” said Jan Rybniker, who heads the translational research unit for infectious diseases at the Cologne Center for Molecular Medicine (CMMC). and launched the study.

In deciphering the exact mechanism of action, the researchers also discovered that some of the newly identified chemicals are molecules with dual activity. Thus, not only do they attack the virulence factors of the pathogen, but they also enhance the activity of monooxygenases, enzymes necessary for the activation of the classic antibiotic ethionamide.

Ethionamide is a drug that has been used to treat tuberculosis for many decades. It is a prodrug, a substance that must be enzymatically activated in the bacteria to kill it. Therefore, the discovered molecules act as prodrug boosters, thus providing another alternative approach to the development of conventional antibiotics.

In cooperation with the research team led by Professor Alain Baulard in Lille, the precise molecular mechanism of this booster effect was deciphered. Thus, in combination with these new active substances, drugs already used against tuberculosis could continue to be used effectively in the future.

This discovery offers several interesting starting points for the development of new agents against tuberculosis, which we urgently need.

“In addition, our work constitutes an interesting example of the diversity of pharmacologically active substances. The activity spectrum of these molecules can be changed by the smallest chemical modifications,” added Rybniker. However, according to scientists, there is still a long way to go before the results are applied in humans, which requires numerous adjustments of substances in the laboratory.