New antibiotic from soil bacteria?

New antibiotic from soil bacteria?

The discovery of how hormone-like molecules turn on antibiotic production in soil bacteria could unlock the untapped opportunities for medicines that are under our very feet.

An international team of scientists have determined the molecular basis of a biological mechanism that could enable more efficient and cost-effective production of existing antibiotics, and also allow scientists to uncover new antibiotics in soil bacteria. It is detailed in a new study published in the journal Nature.

Most clinically used antibiotics are molecules produced by micro-organisms such as bacteria. The majority of these are soil bacteria called Actinobacteria, which are cultivated in the laboratory to allow the molecules they produce to be extracted. However, the production of these molecules is frequently switched off in laboratory cultures, making them difficult to find.

The bacteria tightly control the production of their antibiotics using small molecules akin to hormones. The team investigated a specific class of these bacterial hormones that they had previously discovered, termed 2-akyl-4-hydroxymethylfuran-3-carboxylic acids or AHFCAs, to find out what role they played in controlling the production of an antibiotic in the Actinobacterium Streptomyces coelicolor.

Using x-ray crystallography and single-particle cryo-electron microscopy techniques, they analysed the structure of a protein, known as a transcription factor, bound to a particular region of DNA from the bacterium. This prevents the bacterium from producing the antibiotic.

They then determined the structure of the transcription factor with a synthesized version of one of the AHFCA hormones bound to it, which showed how the DNA is released and antibiotic production is switched on.

Joint lead author said: "Antibiotic resistance is becoming a major issue and we urgently need new antibiotics to tackle it.

"We already know that similar processes control the production of a lot of commercially important molecules. If we understand the mechanisms that control the production of these compounds, we can improve the process, to make it more economically viable.

"It turned out that although we were only looking at one particular class of hormones, the mechanism we found appears to be conserved across all of the different hormone classes in Actinobacteria."

Actinobacteria are more complicated than conventional bacteria. They are generally not motile like other forms of bacteria and they have a complex development cycle that the production of the antibiotics is integrated into.

However, when grown in pure culture these bacteria will often switch off antibiotic production, confounding scientists' efforts to study them. By understanding the molecular mechanism for how this process is controlled, scientists can switch on the production of new antibiotics that are not produced in laboratory cultures.

The author adds: "We can use these strategies to turn on production of new antibiotics in Actinobacteria. Among them, we'd hope to find some that could be useful for tackling infections caused by resistant microbes, as well as other diseases. These compounds would be hard to find via traditional processes."

Key to the discovery was determining the structure of the complex of the transcription factor bound to the DNA, which required the use of single particle cryo-electron microscopy facilities at Monash University to overcome challenges with x-ray crystallography.