Multidrug-resistant bacteria: development of new antibiotics

An increasing number of bacteria are becoming resistant to modern antibiotics, with potentially fatal consequences. This is particularly dangerous in the case of multi-resistant bacteria, which are no longer affected by several antibiotics. A Franco-German research team is aiming to change this. They plan to use novel natural substances that block the vital bacterial enzyme DNA gyrase in an entirely new way to combat even multi-resistant pathogens such as tuberculosis bacteria and gonococci.

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.

In collaboration with the renowned Institut Pasteur in Paris, researchers from Cologne and Saarbrücken are investigating how new natural substances can stop dangerous pathogens, such as tuberculosis bacteria and gonococci (the bacteria responsible for gonorrhoea), even when they are resistant to common drugs.

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. Professors Jan Rybniker and Rolf Müller, both from the German Center for Infection Research (DZIF), are part of the consortium.

The research focuses on DNA gyrase, an enzyme that is essential for bacteria. It plays a key role in replicating bacterial DNA. Without functioning gyrase, bacteria cannot multiply. Two natural substances, cystobactamides and corramycins, block DNA gyrase in a novel way. They are also effective against resistant bacteria because they utilise new binding sites on the enzyme that cannot be reached by other antibiotics. This means that there is no cross-resistance with known antibiotics. As part of the NaPGyr project, the Franco-German team is investigating these new binding sites in more detail.

"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. 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: DZIF