DFG and ANR fund Franco-German „NaPGyr project”
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 NaPGyr, the two researchers associated with the German Center for Infection Research (DZIF), Prof. Dr. Jan Rybniker, Cologne, and Prof. Dr. Rolf Müller, Saarbrücken, are starting a collaboration with the Institut Pasteur in Paris.
Prof. Rybniker is head of the Clinical Infectiology Unit of the Department of Internal Medicine at the University Hospital of Cologne and researcher at the CMMC Center for Molecular Medicine Cologne and coordinates the DZIF's Tuberculosis Research Area. Prof. Rolf Müller is Director of the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and coordinates the DZIF research area "New Antibiotics". Her 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 pathogens, which cannot be controlled even with modern antibiotics, make 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 worldwide, with approximately 87 million cases per year. Both tuberculosis pathogens and gonococci are becoming increasingly resistant or multidrug resistant. 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 novel binding sites on a specific enzyme (DNA gyrase) that is only found in bacteria and is essential for reading and replicating the genetic material of bacteria (DNA synthesis) and thus for their growth. "Gyrases have long been the subject of intense research as a potential molecular target, leading to the development of some initially effective antibiotics known as gyrase inhibitors. However, bacteria have already developed various mechanisms to protect themselves against the existing agents and thus become resistant. It is known from previous research that two natural product classes, cystobactamides and corramycins, are effective in inhibiting DNA synthesis, particularly in Neisseria gonorrhoeae and Mycobacterium tuberculosis, leading to rapid cell death of the bacteria," explains Prof. Rybniker.
The molecular targets of these two classes of compounds are again bacterial topoisomerases, including DNA gyrase. There is much evidence that cystobactamides target a novel binding site or inhibit the bacterial enzymes via a novel mechanism of action. The same is true for corramycins. Important: For both classes of compounds, there appears to be no cross-resistance to already available antibiotics from the group of gyrase inhibitors, which means that these new classes are also effective against resistant bacteria.
The aim of NaPGyr is to structurally characterize the novel binding sites of cystobactamides and corramycins on DNA gyrase. Although the substances are already highly active in the petri dish, they are now to be modified in such a way that they also reach the sites of infection in the body, such as the lungs, in sufficient quantities. The knowledge of the molecular interactions and the mechanism of action will enable the design and synthesis of further and improved derivatives, which can then be used as antibiotics in the treatment of infectious diseases.
Scientific contact Cologne
Professor Dr. Dr. Jan Rybniker
infektiologie-teamassistenz@uk-koeln.de
This message has been modified by the CMMC (K. Heber & D. Grosskopf-Kroiher) and is based on the text provided by the press and communications team of the University Hospital Cologne (original German version here).