idw – Informationsdienst Wissenschaft
Nachrichten, Termine, Experten
Nachrichten, Termine, Experten
HIPS researchers are opening up new avenues for the treatment of multi-resistant pathogens
Antibiotics are a double-edged sword – they should be as toxic as possible to pathogenic bacteria while being harmless to the cells of the human body. An international research team led by the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) has now developed drug candidates that achieve precisely that. The new molecules target a metabolic pathway that only occurs in bacterial cells, thus sparing human cells. The team published its results in the journal Angewandte Chemie International Edition.
Bacterial cells differ fundamentally in their structure from animal and human cells. For example, bacteria have a rigid cell wall, whereas human cells are surrounded only by a simple membrane. If a pharmaceutical agent targets cell wall construction, only bacterial cells are affected. This principle is an important basis for the development of antibiotics, since these should only act on the disease-causing bacteria, but not humans themselves. In their search for new active ingredients, a research team led by HIPS department head Prof. Anna Hirsch has now taken a closer look at a less obvious difference between bacteria and humans that has not yet been pharmaceutically exploited: the so-called methylerythritol phosphate pathway, or MEP pathway for short. The HIPS is a site of the Helmholtz Centre for Infection Research (HZI) in collaboration with Saarland University.
The MEP pathway is an essential part of the energy metabolism of several bacteria, including the hospital germ Pseudomonas aeruginosa. If the MEP pathway in bacteria is blocked, for example by a drug, they can no longer produce a number of vital natural products and subsequently die. Human cells do not have the MEP pathway and would therefore not be affected by a respective drug. In the search for such an active substance, Hirsch's team together with the group of Franck Borel (University of Grenoble) as part of a consortium funded by the European Union has analyzed the individual steps of the MEP in great detail. Their focus was on the enzyme IspD, which is responsible for the third step in the MEP Pathway. The researchers were able to solve the crystal structure of IspD from P. aeruginosa for the first time, thus gaining deep insights into its structural composition. With the help of the information obtained, the team was able to investigate how a specific chemical fragment binds to the enzyme. This so-called complex structure has enabled the design of optimized derivatives that make even better use of the binding pocket and thus bind more strongly to the enzyme.
“The fragments we synthesized bind excellently to their target protein IspD, and their other pharmaceutical properties also offer a promising basis for the development of new active ingredients,” says Eleonora Diamanti, project manager of the consortium and now assistant professor at University of Bologna. Hirsch, who also holds a professorship in medicinal chemistry at Saarland University, says: “What makes the newly developed molecules so special is that they target IspD, a protein that is not addressed by any drug currently on the market. This is the only way to ensure that a potential new antibiotic will also be effective against pathogens that have already become resistant to most conventional drugs.”
Hirsch and her team are currently working on the further development of the new molecules. To this end, they are planning to collaborate closely with the planned excellence cluster nextAID³, in which unexplored targets such as IspD will also play an important role. The next steps include efficacy studies in bacteria and the optimization of efficacy and other pharmaceutical parameters.
This press release is also available on our website: https://www.helmholtz-hzi.de/en/media-center/newsroom/news-detail/targeted-inter...
Helmholtz Institute for Pharmaceutical Research Saarland:
The Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) in Saarbrücken was founded jointly by the HZI and Saarland University in 2009. Scientists at HIPS develop and employ experimental and computational approaches to provide new active substances against infectious diseases, optimise them for use in humans and investigate how they can best be transported to their site of action in the human body. A special focus of the institute is on microbial natural products from soil bacteria and the human microbiota as well as innovative medicinal chemistry-driven approaches. https://www.helmholtz-hips.de
Helmholtz Centre for Infection Research:
Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and its other sites in Germany are engaged in the study of bacterial and viral infections and the body’s defence mechanisms. They have a profound expertise in natural compound research and its exploitation as a valuable source for novel anti-infectives. As member of the Helmholtz Association and the German Center for Infection Research (DZIF) the HZI performs translational research laying the ground for the development of new treatments and vaccines against infectious diseases. https://www.helmholtz-hzi.de/en
Contact:
Dr. Yannic Nonnenmacher
Scientific Strategy Officer
Phone +49 681 98806 4500
yannic.nonnenmacher@helmholtz-hips.de
Daan Willocx, Lucia D'Auria, Danica Walsh, Hugo Scherer, Alaa Alhayek, Mostafa M. Hamed, Franck Borel, Eleonora Diamanti, Anna K. H. Hirsch. Fragment Discovery by X-Ray Crystallographic Screening Targeting the CTP Binding Site of Pseudomonas Aeruginosa IspD. Angewandte Chemie (2025) DOI: 10.1002/anie.202414615
https://doi.org/10.1002/anie.202414615
3D model of the interaction between the enzyme IspD from Pseudomonas aeruginosa and one of the devel ...
HIPS/Diamanti
Criteria of this press release:
Journalists, Scientists and scholars
Biology, Chemistry, Medicine
transregional, national
Research results, Scientific Publications
English
3D model of the interaction between the enzyme IspD from Pseudomonas aeruginosa and one of the devel ...
HIPS/Diamanti
You can combine search terms with and, or and/or not, e.g. Philo not logy.
You can use brackets to separate combinations from each other, e.g. (Philo not logy) or (Psycho and logy).
Coherent groups of words will be located as complete phrases if you put them into quotation marks, e.g. “Federal Republic of Germany”.
You can also use the advanced search without entering search terms. It will then follow the criteria you have selected (e.g. country or subject area).
If you have not selected any criteria in a given category, the entire category will be searched (e.g. all subject areas or all countries).
