Comeback of the biphenomycins

Staphylococcus aureus can trigger a wide range of infections—from skin and postoperative wound infections to pneumonia and life-threatening sepsis—making it one of the most problematic pathogens in clinical settings. Because this bacterium frequently develops resistance to commonly used antibiotics, treatment is increasingly difficult. In Germany alone, roughly 132,000 cases of methicillin-resistant Staphylococcus aureus (MRSA) are reported each year. With drug-resistant S. aureus infections continuing to rise worldwide, new antibiotics capable of overcoming resistance are urgently needed. Biphenomycins, natural products discovered in the 1960s, show strong activity against S. aureus and other Gram-positive pathogens. Despite their potency and good tolerability in animal models, they were never developed into therapeutics—primarily because their natural producer, a Streptomyces strain, only produces them in small amounts that are insufficient for drug development. In addition, the genes responsible for their biosynthesis remained unknown, preventing production in a more suitable host organism. Together with colleagues at TU Dresden, HIPS researchers have now fully elucidated the biosynthetic pathway of the biphenomycins. HIPS is a site of the Helmholtz Centre for Infection Research (HZI) in collaboration with Saarland University.

Elisabeth Strunk, first author of the study and doctoral researcher in the Gulder group, highlights the significance of this achievement: “For the first time, we were able to unravel all enzymatic steps that convert a simple peptide into the biologically active biphenomycin molecule. This understanding of the biosynthetic pathway now provides a basis for targeted improvement of this natural product family.” The study shows that the bacterial producer first synthesizes a simple peptide that contains regions guiding subsequent modifications. Several specialized enzymes then process the peptide in a defined order. Particularly remarkable is the enzyme pair BipEF, which combines two functions in one: it introduces specific chemical groups into the peptide and simultaneously cleaves it at a defined position. Such a dual function has not previously been observed within this enzyme family.

With the biosynthetic pathway now elucidated, the researchers can begin to systematically modify the involved genes and transfer them into more suitable production strains. This paves the way to produce sufficient quantities of biphenomycins for further studies and to generate new variants with improved pharmaceutical properties. “For decades, biphenomycins were scientifically intriguing but practically inaccessible. Now that we understand how they are assembled, we can start to actively engineer them and create entirely new derivatives. This is a crucial step that enables us to develop innovative drug candidates for infections that no longer respond to standard therapies,” says Tobias Gulder, head of the department of Natural Product Biotechnology at HIPS and professor at Saarland University. These findings lay the foundation for future efforts to turn biphenomycins into viable therapeutic options and represent an important contribution to the global search for new solutions to antibiotic resistance.

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/en/

Helmholtz Centre for Infection Research:
Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and other locations in Germany study bacterial and viral infections and the body's defense mechanisms. They have in-depth expertise in natural product research and its use as a valuable source for novel anti-infectives. As a member of the Helmholtz Association and the German Center for Infection Research (DZIF), the HZI conducts translational research to lay the foundations for the development of novel therapies and vaccines against infectious diseases. https://www.helmholtz-hzi.de/en/