Soil bacteria hormone discovery provides fertile ground for new antibiotics

The soil-dwelling Streptomyces coelicolor bacteria producing antibiotics in a Petri dish. Credit: Christophe Corre

An international team of scientists working at the University of Warwick, UK, and Monash University, Australia, 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 today (4 February) 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 at Warwick and Monash 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.

Professor Greg Challis, who co-led the study and has a joint appointment at the University of Warwick and Monash University Biomedicine Discovery Institute (BDI), said: “Only a modest number of structures of this type of protein-DNA complex have been determined using x-ray crystallography over the last few decades due to the challenge of obtaining suitable crystals."

“By using cryo-electron microscopy we have circumvented this challenge, which should make it easier to determine the structures of similar complexes in the future. It wouldn’t have been possible to illuminate the molecular basis for control of antibiotic production by these hormones without the combined expertise of colleagues at Warwick and Monash.”

  • Molecular basis for control of antibiotic production by a bacterial hormone’ will be published in Nature, DOI: 10.1038/s41586-021-03195-x Link: https://www.nature.com/articles/s41586-021-03195-x
  • This research received support from the Royal Society and the Biotechnology and Biological Sciences Research Council, part of UK Research and Innovation.

To read the full press release, visit the Monash BDI news website.