Scientists have uncovered a previously unknown class of natural compounds hidden within soil-dwelling bacteria.
Scientists have discovered a previously unknown group of molecules in soil bacteria that bind to a human protein associated with several types of cancer. The compounds, known as myxoglucamides, have an unusual chemical structure and could provide a starting point for developing new drugs, although researchers have not demonstrated a strong effect on cancer cell growth.
The discovery emerged from two studies examining how bacteria produce these molecules and how they interact with human cells. Myxoglucamides combine molecular components derived from sugars, lipids, and amino acids in an arrangement unlike previously known natural products. Accessing them required researchers to activate bacterial genes that normally remain silent.
Unlocking Hidden Chemistry in Soil Bacteria
Myxoglucamides are produced by myxobacteria, a group of soil-dwelling microorganisms known for synthesizing diverse biologically active compounds. Using modern genetic techniques, scientists at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) activated a previously silent biosynthetic pathway, allowing them to produce and detect the molecules.
The team then examined the biosynthetic gene cluster responsible for their production and traced the biochemical reactions involved. Their analysis identified a previously unknown pathway in which several enzymes work together in an unexpected sequence to assemble the compounds’ distinctive chemical structure. The findings could help researchers locate other natural products concealed within inactive microbial genes.
“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 initial discovery and structural characterization were carried out by a team led by Prof. Rolf Müller, scientific director of HIPS and head of its Department of Microbial Natural Products.
Recreating a Rare Bacterial Molecule in the Laboratory
Because the bacteria naturally produce only tiny amounts of myxoglucamides, researchers needed another way to obtain enough material for biological testing. In the second study, they achieved the first total laboratory synthesis of myxoglucamide A, making it possible to investigate the compound and prepare chemically modified versions.
Some of these synthetic derivatives bound substantially more strongly than the original molecule to a human protein called AKR1C3. Using a method that systematically identifies which cellular proteins interact with a compound, the researchers established AKR1C3 as the primary binding target of myxoglucamides.
AKR1C3 participates in the production of certain hormones and inflammatory signaling molecules. It is also overproduced in several cancers, where it can contribute to tumor cell growth. Although binding to this protein suggests a potential direction for anticancer drug development, the experiments did not establish that myxoglucamides strongly inhibit cancer cell growth.
“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 Prof 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.”
References:
“Atypical Condensation Domains Guide Discovery and Illuminate Biosynthesis of Myxoglucamides Featuring Vinyl-Substituted, α-Oxidized γ-Amino Acids” by Tingting Wang, Alexander Popoff, Maja Hunter, Guangzhi Dai, Ronald Garcia, Huixin Xu, Haowen Zhao, Asfandyar Sikandar, Liujie Huo, Rolf Müller and Chengzhang Fu, 7 August 2026, Angewandte Chemie International Edition.
DOI: 10.1002/anie.6995139
“Synthesis and Activity-Based Protein Profiling Identifies Aldo-Keto Reductase 1C3 as Target Protein of Myxoglucamides” by Thomas Siemon, Vivek K. Mishra, Mingming Zhao, Konrad Büssow, Alexander Popoff, Chengzhang Fu, Rolf Müller, Lothar Jänsch, Wulf Blankenfeldt and Mark Brönstrup, 10 August 2026, Angewandte Chemie International Edition.
DOI: 10.1002/anie.6489568
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