Multi-resistant bacteria: development of new antibiotics

Electron micrograph of Mycobacterium tuberculosis.

© CDC/Alissa Eckert; James Archer

The German Research Foundation (DFG) and the French Agence National de la Recherche (ANR) are now funding the project "Characterization of novel natural product binding sites in the DNA gyrase of multidrug-resistant Mycobacterium tuberculosis and Neisseria gonorrhoeae (NaPGyr)", in which a new consortium is researching the development of antibiotics against multidrug-resistant bacteria. In NaPGyr, Prof. Jan Rybniker and Prof. Rolf Müller—both scientists in the German Center for Infection Research (DZIF)—are starting a collaboration with the Institut Pasteur in Paris.

Prof. Rybniker is head of the Division of Infectious Diseases at the University Hospital of Cologne and deputy coordinator of the Tuberculosis research area at the DZIF. Prof. Rolf Müller is Director of the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and coordinates the research area Novel Antibiotics at the DZIF. Their project partner at the Institut Pasteur is structural biologist Dr. Stéphanie Petrella.

Antibiotic resistance is one of the greatest challenges facing medicine today. Multi-resistant bacteria that cannot be controlled by modern antibiotics are making it increasingly difficult to treat patients with bacterial infections. Tuberculosis is one of the world's leading causes of death, affecting more than ten million people each year and causing an estimated 1.4 million deaths. Gonococci cause urethral inflammation (gonorrhea), which, according to the World Health Organization (WHO), is one of the most common sexually transmitted diseases in the world, with approximately 87 million cases per year. Both tuberculosis pathogens and gonococci are becoming increasingly resistant to multiple drugs. New approaches and the development of novel compounds against these pathogens are therefore of paramount importance.

In the NaPGyr project, funded by the DFG and the ANR, German and French researchers are now working on the comprehensive characterization of new binding sites of a specific enzyme (DNA gyrase) that is only found in bacteria and is essential for reading and replicating the bacterial genome (DNA synthesis) and thus for the growth of bacteria. "Gyrases as potential molecular targets have long been the subject of intense research, leading to the development of some initially effective antibiotics, so-called gyrase inhibitors. However, bacteria have already developed various mechanisms to protect themselves against the available agents and become resistant. Previous research has shown that two classes of natural products, cystobactamides and corramycins, are effective inhibitors of DNA synthesis, particularly in Neisseria gonorrhoeae and Mycobacterium tuberculosis, leading to rapid cell death of the bacteria," explains Prof. Rybniker.

The molecular targets of both classes are bacterial topoisomerases, including DNA gyrase. There is strong evidence that the cystobactamides act at a novel binding site or inhibit the bacterial enzymes via a novel mechanism of action. The same is true for the corramycins. Important: For both classes of compounds, there appears to be no cross-resistance to existing antibiotics in the group of gyrase inhibitors, which means that these new compound classes are also effective against resistant bacteria.

The NaPGyr project aims to structurally characterize the novel binding sites on DNA gyrase that are targeted by cystobactamides and corramycins. Although the substances are already highly active in the petri dish, they are now to be modified in such a way that they reach the infection sites in the body, e.g. the lungs, in sufficient quantities. Knowledge of the molecular interactions and the mechanism of action will enable the design and synthesis of further and improved derivatives, which can then potentially be used as antibiotics in the treatment of infectious diseases.

Source: Press release of the University Hospital Cologne (translated from German)