Bacteria have been manufacturing complex chemicals with remarkable precision for millions of years. Scientists studying this microscopic chemistry have now identified how bacterial molecular machinery can exchange components to produce different compounds with anti-cancer properties, offering a potential blueprint for developing new drugs.
The research out of the University of Warwick, located on the outskirts of Coventry, a historic manufacturing hub in the heart of England, centres on specialised molecular assemblies within bacteria that manufacture chemicals known as natural products. These assemblies comprise multiple proteins that must interact with one another in a precise sequence to produce a particular molecule.
Munro Passmore, lead author of the study, and his colleagues identified specialised protein regions that act as adapters, enabling different components of these bacterial assemblies to recognise and interact with one another. By examining four related biosynthetic pathways, the researchers found natural examples of bacteria swapping components of the machinery to produce different chemical compounds.
The compounds include romidepsin, an anti-cancer drug approved for treating certain blood cancers, alongside three other related natural products. While three of the molecules had been identified previously, with the fourth characterised in this study, the mechanisms through which bacteria manufacture them had not been investigated in this way.
The discovery offers researchers a starting point for understanding how these molecular components can be exchanged without disrupting the machinery. The key, Passmore explains, lies in identifying the small regions of proteins responsible for their interactions.
"It is all about the shape and the charges between them. Some are positively charged or negatively charged, kind of like a battery or a magnet, and it is really small changes that have this effect," Passmore explains. "If you think about it on the scale of maybe one in 200 [amino acids] being important for this specific interaction, it takes a lot of work for us to work that out."
The research, which began approximately eight years ago, has involved 15 to 20 direct contributors. Passmore has personally worked on the project for six years. The next step is to identify which parts of the protein structures must remain unchanged for the machinery to function, and which can be modified.
"What would be really great is to be able to develop our own anti-cancer drugs based on this principle," Passmore says. "We could use the bacterial machinery to make new products, new chemicals that are more effective or more specific than the currently available treatments."
Computational tools are assisting this work. Passmore cites AlphaFold, an artificial intelligence-based protein structure prediction system, as particularly useful in predicting the physical structures of proteins and their binding complexes. What previously could have taken months of experimental work can now be visualised in an afternoon. However, predictions still require laboratory verification.
For now, the prospect of designing new anti-cancer drugs using this principle remains a long-term research goal. The immediate task is to understand the molecular rules that bacteria seem to have already mastered.
