Treating tuberculosis when antibiotics no longer work

A research team has detected various substances that have a dual effect against tuberculosis: They render the bacteria causing the disease less pathogenic for human immune cells and boost the activity of conventional antibiotics.

Tuberculosis is currently the infectious disease that causes the most deaths worldwide. Of particular concern is the increasing emergence of multidrug-resistant tuberculosis bacteria, particularly in Eastern Europe and Asia. In cooperation with research partners in France, the infectious disease specialist Dr Jan Rybniker and his team at University Hospital Cologne, the University of Cologne’s Faculty of Medicine and the German Center for Infection Research (DZIF) have identified new antibiotic molecules that target Mycobacterium tuberculosis and make it less pathogenic for humans. In addition, some of the discovered substances may allow for a renewed treatment of tuberculosis with available medicationsincluding strains of the bacterium that have already developed drug resistance. The research has now been published in Cell Chemical Biology.

Tuberculosis (TB)or "consumption", as it used to be calledmainly 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 still ranks among the infectious diseases that claim the most lives worldwide: According to the World Health Organisation (WHO), only Covid-19 was deadlier than TB in 2022. The disease also caused almost twice as many deaths as HIV/AIDS. More than 10 million people continue to contract TB every year. This is mainly due to insufficient access to medical treatment in many countries.

Limited targets

Multidrug-resistant tuberculosis is emerging especially in eastern Europe and Asia. That is of particular concern to researchers because like all bacteria that infect humans, M. tuberculosis possesses only a limited number of targets for conventional antibiotics. That makes it increasingly difficult to discover new antibiotic substances in research laboratories.

Working together with colleagues from the Institute Pasteur in Lille, France, and the German Center for Infection Research (DZIF), the researchers at University Hospital Cologne have now identified an alternative treatment strategy for the bacterium. The team utilised host-cell-based high-throughput methods to test the ability of molecules to inhibit the multiplication of bacteria in human immune cells: From a total of 10,000 molecules, this procedure allowed them to isolate a handful whose properties they scrutinised more closely in the course of the study.

Double attack

Ultimately, the researchers identified virulence blockers that utilise target structures that are fundamentally distinct from those targeted by classical antibiotics. “These molecules probably lead to significantly less selective pressure on the bacterium, and thus to less resistance,” says Jan Rybniker, deputy coordinator of the DZIF research area Tuberculosis and head of the Translational Research Unit for Infectious Diseases at the Center for Molecular Medicine Cologne, who initiated the study.

In deciphering the exact mechanism of action, the researchers also discovered that some of the newly identified chemical substances are dual-active molecules. Thus, they not only attack the pathogen’s virulence factors, but also enhance the activity of monooxygenasesenzymes required for the activation of the conventional antibiotic ethionamide. Ethionamide is a drug that has been used for many decades to treat TB. It is a so-called prodrug, a substance that needs to be enzymatically activated in the bacterium to kill it. Therefore, the discovered molecules act as prodrug boosters, providing another alternative approach to the development of conventional antibiotics. In cooperation with the research team led by Prof. Alain Baulard at Lille, the precise molecular mechanism of this booster effect was deciphered. Thus, in combination with these new active substances, drugs that are already in use against tuberculosis might continue to be employed effectively in the future.

The discovery offers several attractive starting points for the development of novel and urgently needed agents against tuberculosis. “Moreover, our work is an interesting example of the diversity of pharmacologically active substances. The activity spectrum of these molecules can be modified by the smallest chemical modifications,” Rybniker adds. However, according to the scientists it is still a long way to the application of the findings in humans, requiring numerous adjustments of the substances in the laboratory.

Source: Press release of the University of Cologne

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