Bacteria Mycobacterium tuberculosis, the causative agent of tuberculosis, 3D image copyright: Kateryna Kon - shutterstock.com
"The discovery provides promising starting points for developing new compounds to combat tuberculosis. Our work is an interesting example of the diversity of pharmacologically active substances. The discovered molecules act as prodrug boosters, providing another alternative approach to the development of conventional antibiotics,” says Jan Rybniker.
In cooperation with research partners in Germany and France, the infectious disease specialist Dr Dr Jan Rybniker and his team at University Hospital Cologne and the University of Cologne’s Faculty of Medicine 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 medications – including strains of the bacterium that have already developed drug resistance. The research has been published in the article "Discovery of dual-active ethionamide boosters inhibiting the Mycobacterium tuberculosis ESX-1 secretion system" in Cell Chemical Biology - https://doi.org/10.1016/j.chembiol.2023.12.007
Tuberculosis (TB) mainly affects the lungs but can also damage other organs. It is curable if diagnosed early and treated with antibiotics. Although relatively rare in most Western European countries, it remains one of the deadliest infectious diseases worldwide. In 2022, only Covid-19 claimed more lives than TB, according to the World Health Organization (WHO). TB causes almost twice as many deaths as HIV/AIDS. Over 10 million people contract TB annually due to inadequate medical treatment in many countries.
Limited targets
Multidrug-resistant tuberculosis is a growing problem, particularly in Eastern Europe and Asia. Mycobacterium tuberculosis, like all bacteria that infect humans, has a limited number of targets for conventional antibiotics, making 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 utilized host-cell-based high-throughput methods to test the ability of molecules to stem 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 scrutinized more closely in the course of the study.
Double attack
Ultimately, the researchers identified virulence blockers that utilize 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,” said Jan Rybniker, who heads the Translational Research Unit for Infectious Diseases at the Clinic I of Internal Medicine as well as a research project B 10 at the Center for Molecular Medicine Cologne (CMMC) and 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 monooxygenases – enzymes 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 Professor 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 provides promising starting points for developing new agents to combat 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 added. 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.
This research was made possible with the support of the German Center for Infection Research (DZIF) and other funding institutions.
Publication:
Gries et al.: "Discovery of dual-active ethionamide boosters inhibiting the Mycobacterium tuberculosis ESX-1 secretion system“, Cell Chemical Biology. - https://doi.org/10.1016/j.chembiol.2023.12.007
Contact
Dr Dr Jan Rybniker
Clinict I of Internal Medicine, University Hospital Cologne and
Center for Molecular Medicine Cologne (CMMC)
jan.rybnikeruk-koeln.de
Press Release by the Press and Communications Team of the University of Cologne:
Eva Schissler - e.schisslerverw.uni-koeln.de
Copyright ©
Prof. Dr. med. Thomas Benzing
Chair of the CMMC
