Silent bacterial genes yield potential leads for future cancer drugs

Silent bacterial genes yield potential leads for future cancer drugs Sadie Harley Scientific Editor Robert Egan Senior Editor Natural products produced by microorganisms are a promising source of new drugs. Researchers at the Helmholtz Center for Infection Research (HZI) and its Saarbrücken-based site, the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), have now discovered a new family of such compounds, elucidated their unusual biosynthesis and developed a way to produce them synthetically. They also found that this class of compounds binds specifically to a human protein involved in the development of cancer. The findings were published in two thematically linked studies in Angewandte Chemie International Edition. Activating a silent biosynthetic pathway The two studies focus on so-called myxoglucamides, which are produced by soil-dwelling myxobacteria. These bacteria are known for generating a diversity of natural products, many of which show biological activity. In the first study, using modern genetic methods, the team succeeded in specifically activating the biosynthetic pathway for myxoglucamides that had remained silent in the bacteria. This was the key to producing and detecting the compounds in the first place. What makes myxoglucamides particularly interesting is their unusual structure: They combine building blocks derived from sugars, lipids and amino acids in a way that clearly sets them apart from previously known natural products. HIPS is a site of the Helmholtz Center for Infection Research in collaboration with Saarland University. An unexpected route to complex molecules The researchers also investigated how these molecules are assembled in the bacteria. To do so, they analyzed the underlying genetic blueprint—the so-called biosynthetic gene cluster—as well as the individual biochemical steps required for myxoglucamide production. Their work revealed a previously unknown biosynthetic pathway. Several enzymes act together in an unexpected way, generating a chemical structure that had not been described before in this form. The study thus provides new insights into how microorganisms construct complex natural products and how such hidden compounds may be identified more systematically in the future. "The discovery of myxoglucamides highlights how much chemical potential remains hidden in previously silent biosynthetic gene clusters of microorganisms," says Dr. Chengzhang Fu, head of the junior research group "Genome Mining for Secondary Metabolites" at HIPS. "By selectively activating and deciphering these biosynthetic pathways, we can gain access to entirely new natural products." The team led by Rolf Müller, scientific director of HIPS and head of the department "Microbial Natural Products," was responsible for the initial discovery of the molecule and the determination of its structure. "The unusual building block produced by the bacteria opens up new avenues for research: Such molecular components can help in the development of more targeted drugs. Nature has found ways here that we were previously unaware of," says Müller. Synthetic production enables target testing In the second study, the team explored the molecular targets of myxoglucamides in human cells. To this end, the researchers achieved the first total synthesis of myxoglucamide A in the laboratory. This was a crucial step, as the myxobacterial producer generates the compound only in very small amounts, which were insufficient for further investigations. The synthetic route also enabled the team to test slightly modified variants and better understand which parts of the molecule are important for its activity. Some of these synthetic derivatives bound the target protein much more strongly than the natural compound. Using a method that systematically identifies the proteins a molecule binds to in the cell, the researchers showed that myxoglucamides interact primarily with the human protein AKR1C3. A cancer-linked target, with caveats AKR1C3 is an enzyme involved in the production of certain hormones and inflammatory signaling molecules. It is also known to be overproduced in several types of cancer, where it can promote tumor cell growth. The fact that myxoglucamides bind to this protein makes them a potential starting point for the development of novel anticancer drugs. "Although we were unable to demonstrate a strong effect of myxoglucamides on cancer cell growth, the study nevertheless shows that natural products without an immediately obvious biological effect can still engage highly relevant targets in the human body," says Mark Brönstrup, head of the department "Chemical Biology" at HZI. "This is exactly where great potential lies for identifying new concepts for the development of innovative drugs." Publication details Tingting Wang et al., Atypical Condensation Domains Guide Discovery and Illuminate Biosynthesis of Myxoglucamides Featuring Vinyl‐Substituted, α‐Oxidized γ‐Amino Acids, Angewandte Chemie International Edition (2026). DOI: 10.1002/anie.6995139 Thomas Siemon et al., Synthesis and Activity‐Based Protein Profiling Identifies Aldo‐Keto Reductase 1C3 as Target Protein of Myxoglucamides, Angewandte Chemie International Edition (2026). DOI: 10.1002/anie.6489568 Journal information: Angewandte Chemie International Edition Provided by Helmholtz Association of German Research Centres