The lack of new antibiotics threatens global efforts to contain drug-resistant infections. Researchers from the University of Warwick in the U.K., and Monash University in 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.

Their findings were published in the journal Nature in a paper titled, “Molecular basis for control of antibiotic production by a bacterial hormone.”

Most clinically used antibiotics are molecules produced by microorganisms such as bacteria. The majority of these are soil bacteria called Actinobacteria.

“Actinobacteria produce numerous antibiotics and other specialized metabolites that have important applications in medicine and agriculture. Diffusible hormones frequently control the production of such metabolites by binding TetR family transcriptional repressors (TFTRs), but the molecular basis for this remains unclear,” the investigators wrote.

The researchers 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.

The researchers used x-ray crystallography and single-particle cryo-electron microscopy to analyze the structure of a protein, called transcription factor, bound to a particular region of DNA from the bacterium. The researchers 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.

“Antibiotic resistance is becoming a major issue and we urgently need new antibiotics to tackle it,” explained Chris Corre, PhD, associate professor of synthetic biology at the University of Warwick, departments of life sciences and chemistry. “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.”

When Actinobacteria are grown in pure culture, they will often switch off antibiotic production. 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.

“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,” added Corre.

By using cryo-electron microscopy the researchers overcame the hurdle, which should allow more ease to determine the structures of similar complexes in the future.

These findings will facilitate the use of actinobacterial hormones and their associated TFTRs in synthetic biology and in the discovery of new antibiotics. These findings unlock the untapped opportunities for antibiotics that are under our very feet.

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