30.09.2026
A new mechanism of action against an old enemy
Natural compound from soil bacteria opens up a new approach to treating drug-resistant tuberculosis.
Press Release DZIF, 23.09.2026. According to the World Health Organization (WHO), tuberculosis (TB) affects more than 10 million people and causes over a million deaths each year, making it one of the world’s deadliest infectious diseases. Treatment is lengthy and typically involves taking a combination of antibiotics for several months. Drug-resistant Mycobacterium tuberculosis strains are particularly problematic because the antibiotics used are only partially effective against them. Therefore, new active compounds capable of overcoming existing resistance are urgently needed. An international team led by the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), the Institut Pasteur, Université Paris Cité, and the University Hospital Cologne has now demonstrated that the natural compound corramycin attacks M. tuberculosis in a novel way, exhibiting a previously unknown effect against the pathogen. The researchers published their findings in the journal Advanced Science.
The study began with the screening of an extensive library of myxobacterial extracts against the tuberculosis pathogen, M. tuberculosis. During this process, the researchers identified corramycin as a promising candidate. In laboratory tests, this natural compound was found to be effective against various strains of the tuberculosis pathogen, including strains from clinical samples that are resistant to commonly used antibiotics. These results suggest that corramycin may be effective where established drugs reach their limits. The study was conducted in close collaboration between HIPS and Dr. Stéphanie Petrella of the Institut Pasteur (Paris, France) and Université Paris Cité, as well as partners from the German Center for Infection Research (DZIF). The DZIF partners included research groups led by Prof. Jan Rybniker of the University Hospital Cologne and Prof. Norbert Reiling of the Research Center Borstel, Leibniz Lung Center. HIPS is a site of the Helmholtz Centre for Infection Research in collaboration with Saarland University.
“We already knew that corramycin is a naturally occurring substance with antibiotic activity. What’s new is that we’ve now been able to demonstrate its pronounced activity against Mycobacterium tuberculosis and, at the same time, elucidate how the substance damages the pathogen,” says Dr. Franziska Fries, a researcher in the department “Microbial Natural Products” at HIPS. “What’s particularly exciting is that corramycin attacks its cellular target, DNA gyrase, in a different way than fluoroquinolones—antibiotics already in clinical use that also target DNA gyrase. This also explains why corramycin remains effective against fluoroquinolone-resistant bacteria.”
DNA gyrase is an enzyme that bacteria need to replicate their genetic material. The research team was able to show that corramycin not only inhibits this enzyme but also puts it in a state that harms the bacterium. The natural compound binds to the gyrase after it has cut the DNA, preventing the enzyme from rejoining the DNA strands correctly. This severely damages the bacterium’s genetic material, ultimately leading to its death. Cryo-electron microscopy provided important insights into this mechanism. With its help, the researchers were able to visualize exactly how corramycin binds to DNA gyrase.
“This project shows exactly what a cutting-edge technology like cryo-EM can achieve. It gave us the key information needed to confirm the target and unravel the mode of action of this natural product,” says Dr. Stéphanie Petrella, co-last author of the study and Associate Professor at Université Paris Cité, hosted for her research at the Institut Pasteur.
Corramycin was previously investigated in a development program in collaboration with Sanofi/Evotec. At that time, the focus was on Gram-negative bacteria that cause urinary tract infections. Despite its apparent pharmaceutical potential, further development was not pursued at the time due to high production costs. However, corramycin’s activity demonstrated against M. tuberculosis provides reason to revisit corramycin under new circumstances.
“Our results show that corramycin is a promising starting point for the development of new active compounds against drug-resistant tuberculosis,” says Prof. Rolf Müller, scientific director of HIPS and head of the research group Microbial Natural Products. Müller is also a researcher in the Novel Antibiotics research area at DZIF. “However, before it can be developed into a drug, the production of the substance, its activity in the human body, and its pharmacokinetic properties, in particular, must be further optimized.”
Thus, the study not only provides an explanation for corramycin’s antituberculous effect, but also establishes an important foundation for the further development of this class of natural products. At the same time, it demonstrates the potential of microbial natural products in the search for new mechanisms of action to combat drug-resistant pathogens.
“This project demonstrates the strength of collaborative research, both within DZIF and internationally,” concludes Prof. Jan Rybniker, head of the Division of Infectious Diseases at University Hospital Cologne and deputy coordinator of the DZIF research area Tuberculosis.