Hospital-acquired germ MRSA: New antibiotic discovered

The health risks posed by the increasing spread of multidrug-resistant bacteria, commonly called "hospital germs," have gained increasing public attention in recent years. They are particularly dangerous for patients in hospitals. Together with a partner, the French company DEINOVE, a team of scientists from the Department of Biological Chemistry led by Prof. Dr. Roderich Süssmuth from TU Berlin has now discovered a new class of lipopeptide antibiotics that show promising activity against multidrug-resistant bacteria. The results have been published in the latest issue of the scientific journal Nature Chemical Biology.

As reported by Roderich Süssmuth's research group in the renowned journal Nature Chemical Biology, another active compound class targeting these multidrug-resistant bacteria has been found. These so-called "hospital germs" are very common in clinical settings and pose a particular threat to patients. Although there are already many bacteria that are resistant to multiple antibiotics, Methicillin-resistant Staphylococcus aureus, or MRSA, is one of the most well-known. It can be deadly, especially for patients with weakened immune systems. Due to resistance against common antibiotics, these infections are difficult or impossible to treat. Reports of initial "completely resistant" infections highlight the great medical and societal importance of developing new antibiotics that differ fundamentally from those already in use through new "lead structures."

In the race for limited resources, microorganisms compete with each other in nature

In cooperation with the French company DEINOVE, a collection of bacterial strains was examined for the production of molecules with antibacterial activity. Successfully, because from a culture of the bacterium Microbacterium arborescens, a compound with strong activity against MRSA and other pathogenic bacteria was isolated. "Bacteria and fungi are a very good source of bioactive compounds because in the competition for limited resources, microorganisms fight each other in nature. We can use this to our advantage," explains Roderich Süssmuth.

Within the framework of a project funded by the German Research Foundation (DFG), the chemical structure of the molecule later called Microvionin was first elucidated, and its biosynthesis was reconstructed in the laboratory. During this process, the scientists discovered something unexpected: Microvionin consists of a peptide and a fatty acid part, with three of the amino acids modified so that two ring structures form, making it "bicyclic." Due to this characteristic structural feature with a thioether bridge, Microvionin can be classified among the so-called lanthipeptides, a class of ribosomally synthesized and post-translationally modified peptides (RiPPs). In several series of experiments, the researchers were able to trace the cyclization of the molecule and show that this occurs through the close cooperation of two enzymes, thus preventing the formation of unwanted side products. "What also interests us is the rather unusual fatty acid modification. Here, for the first time in ribosomally synthesized peptides, two biosynthesis pathways seem to converge—namely, ribosomally synthesized peptides and polyketide synthases—whose interaction has not been observed before. This is naturally exciting for us and will continue to be intensively researched," explains Roderich Süssmuth.

More than ten genetically similar compounds exist in nature – potential candidates for new antibiotics

Primarily because of the unexpected structure and biosynthesis, the scientists wanted to find out whether there are other similar compounds in nature. Using so-called "genome mining," bacterial genomes are analyzed with the aim of discovering specific biosynthesis gene clusters. The team led by Roderich Süssmuth also made such findings. More than ten potential candidates were identified. From one of these strains, another related molecule called "Nocavionin" was isolated. Roderich Süssmuth is confident that the group of antibiotics now called "Lipolanthines" will soon expand further: "Of course, we are now also trying to isolate the other molecules and determine correlations between their structures and bioactivity. Additionally, elucidating the remaining steps of biosynthesis is very interesting for us. Ultimately, we also hope to advance the development of Microvionin into a usable drug. We are just at the beginning of this project, and I am curious to see how it will develop from here."

The article in Nature Chemical Biology:

"The anti-staphylococcal lipolanthines are ribosomally synthesized lipopeptides"
Vincent Wiebach, Andi Mainz, Mary-Ann J. Siegert, Natalia A. Jungmann, Guillaume Lesquame, Sophie Tirat, Assia Dreux-Zigha, Jozsef Aszodi, Dominique Le Beller & Roderich D. Süssmuth

Nature Chemical Biology volume 14, pages 652–654 (2018), DOI: 10.1038/s41589-018-0068-6