In collaboration with research partners in Germany and France, researchers discovered new antibiotic molecules that target Mycobacterium tuberculosis and make it less pathogenic for humans. The findings were published in Cell Chemical Biology as 'Discovery of dual-active ethionamide boosters blocking the Mycobacterium tuberculosis ESX-1 secretion pathway.'
Tuberculosis (TB) mainly 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 Organization (WHO), only Covid-19 was deadlier than TB in 2022.
Researchers at the University Hospital Cologne worked with colleagues from the Institute Pasteur in Lille, France, and the German Center for Infection Research (DZIF). They have now identified an alternative treatment strategy for the bacterium.
In their study, the researchers identified virulence blockers that utilize target structures 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 Center for Molecular Medicine Cologne (CMMC) and initiated the study.
They also discovered that some newly identified chemical substances are dual-active molecules. Thus, they attack the pathogen's virulence factors and enhance the activity of monooxygenases - enzymes required to activate the conventional antibiotic ethionamide.
Ethionamide is a drug that has been used for many decades to treat TB. It is a so-called prodrug 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 developing 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, combined with these new active substances, drugs already used against tuberculosis might continue to be employed effectively in the future.