Researchers from different countries have jointly discovered a new antibiotic

More and more bacterial pathogens are developing resistance. There is an increasing risk that common drugs will no longer be effective against infectious diseases. Scientists around the world are therefore searching for new active substances. Researchers from the University of Bonn, the German Centre for Infection Research (DZIF), the University of Utrecht (Netherlands), Northeastern University in Boston (USA) and NovoBiotic Pharmaceuticals in Cambridge (USA) have now jointly discovered a new antibiotic and elucidated its mode of action. Clovibactin comes from a soil bacterium. This antibiotic is highly effective in attacking the cell wall of bacteria, including many multi-resistant hospital germs. The results are published in the journal “Cell”.

“We urgently need new antibiotics to survive in the race against bacteria that have become resistant,

says Prof Dr Tanja Schneider from the Institute of Pharmaceutical Microbiology at the University of Bonn and the University Hospital Bonn. Not many new substances to combat bacterial pathogens have come onto the market in recent decades. “Clovibactin is new compared to the current antibiotics”, says the co-spokesperson of the Transregional Collaborative Research Centre “Antibiotic CellMAP”, who is also a member of the transdisciplinary research area “Life & Health” and the Cluster of Excellence “ImmunoSensation2”. The Institute of Pharmaceutical Microbiology, together with the German Centre for Infection Research, specialises in deciphering the mode of action of antibiotic candidates.

The soil bacterium Eleftheria terrae subspecies carolina bears its place of origin in its name: It was isolated from a soil sample in the US state of North Carolina and produces the new active ingredient clovibactin to protect itself from competing bacteria. “The new antibiotic attacks the structure of the bacterial cell wall in several places at the same time by blocking essential building blocks”, says Tanja Schneider. With unusual intensity, it attaches itself specifically to these building blocks and kills the bacteria by destroying their cell membranes.

Clovibactin envelops the target structure like a cage
The research groups from different disciplines and countries have worked together to discover exactly how this works. The team led by Prof Kim Lewis from the Antimicrobial Discovery Center at Northeastern University in Boston (USA) and the company NovoBiotic Pharmaceuticals in Cambridge (USA) have discovered clovibactin using the „iCHip“-apparatus. This allows bacteria to be grown in the laboratory that were previously considered uncultivable and were not available for the development of new antibiotics.

“Our discovery of this exciting new antibiotic validates the iCHip cultivation technology in the search for new therapeutic agents from previously uncultured microorganisms,

says Dr Dallas Hughes, President of NovoBiotic Pharmaceuticals, LLC. The company has shown that Clovibactin has very good activity against a broad spectrum of bacterial pathogens and has successfully treated m use in model studies.

The researchers led by Tanja Schneider have elucidated the mechanism of action of the new antibiotic. The Bonn researchers were able to show that clovibactin binds to pyrophosphate groups of bacterial cell wall components in a very targeted and highly specific manner. The group led by Prof Markus Weingarth from the Department of Chemistry at the University of Utrecht in the Netherlands has discovered exactly what this binding looks like. Using solid-state NMR spectroscopy, the researchers have deciphered the structure of the complex of clovibactin and the bacterial target structure lipid II - under conditions similar to those found in bacterial cells. These investigations showed that clovibactin acts around the pyrophosphate group. Hence the name “Clovibactin”, derived from the Greek “Klouvi” (Käfig), because it encloses the target structure like a Käfig.

What does Clovibactin do?
Clovibactin acts primarily on gram-positive bacteria. These include MRSA, known as “hospital germs”, as well as the pathogens that cause widespread tuberculosis, which affects many millions of people worldwide. “We are very confident that the bacteria will not develop resistance to Clovibactin so quickly,” says Tanja Schneider. This is because the pathogens cannot easily change the cell wall components to undermine the effect of the antibiotic.

But Clovibactin can do even more. After docking onto the target structures, clovibactin forms supramolecular fibre-like structures that firmly enclose the target structures and further damage the bacterial cells. Bacteria that encounter clovibactin are also stimulated to release certain enzymes - so-called autolysins - which now dissolve their own cell envelope in an uncontrolled manner. The combination of these different mechanisms is the reason for the extraordinary resistance to resistance," says Tanja Schneider. This shows the potential that still lies in the natural diversity of bacteria that can be used for new antibiotics.

“Without the interdisciplinary cooperation between the partners, this important step in the fight against resistance would not have been possible,

says Prof Markus Weingarth. The research team now wants to use its findings to further increase the effectiveness of Clovibactin. “But there is still a long way to go before the new antibiotic reaches the market,” says Tanja Schneider.

Institutions involved and funding
In addition to the Institute of Pharmaceutical Microbiology and the Clausius Institute for Physical and Theoretical Chemistry at the University of Bonn, other institutions involved in this study were Utrecht University (Netherlands), NovoBiotic Pharmaceuticals in Cambridge (USA), the Rijksuniversiteit Groningen (Netherlands), the University of Tübingen (Germany) and the University of Bonn (Germany);t Tübingen, the German Centre for Infection Research, Tianjin Medical University (China), the Novartis Institutes for Biomedical Research in Cambridge (USA), the University of Florence (Italy), the Consorzio Interuniversitario Risonanze Magnetiche Metallo-Proteine in Sesto Fiorentino (Italy) and Northeastern University in Boston (USA). The German Centre for Infection Research and the Transregio SFB TRR 261 “Antibiotic CellMAP” of the German Research Foundation funded the project on the Bonn and Tübingen side.

Publication
Rhythm Shukla, Aaron J. Peoples, Kevin C. Ludwig, Sourav Maity, Maik G.N. Derks, Stefania De Benedetti, Annika M Krueger, Bram J.A. Vermeulen, Theresa Harbig, Francesca Lavore, Raj Kumar, Rodrigo V. Honorato, Fabian Grein, Kay Nieselt, Yangping Liu, Alexandre Bonvin, Marc Baldus, Ulrich Kubitscheck, Eefjan Breukink, Catherine Achorn, Anthony Nitti, Christopher J. Schwalen, Amy L. Spoering, Losee Lucy Ling, Dallas Hughes, Moreno Lelli, Wouter H. Roos, Kim Lewis, Tanja Schneider, Markus Weingarth: A new antibiotic from an uncultured bacterium binds to an immutable target, Cell, DOI: 10.1016/j.cell.2023.07.038; https://doi.org/10.1016/j.cell.2023.07.038

Article from "LABO" dated 23/08/2023