Understanding the regulation of antibiotic production in Streptomyces: from nature to the clinic.

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The Microbiology Society is undertaking a project entitled A Sustainable Future as part of our 75th Anniversary, which aims to highlight the Sustainable Development Goals (SDGs) to our members and empower them to use their research to evidence and impact the goals. Earlier this year, we put a call out to our members to submit case studies in the following three areas: antimicrobial resistance, soil health and the circular economy.

This case study is written by Dr Lorena Fernández-Martínez, who is a Reader in Microbial Genetics at Edge Hill University and a member of the Microbiology Society. It focuses on antimicrobial resistance; a naturally occurring process, whereby micro-organisms (bacteria, viruses, fungi and parasites) can change and adapt over time, either by modifying the target of the antimicrobial, or by developing and exchanging resistance genes.

Introduction to the project

The increasing incidence of antibiotic resistant bacterial pathogens has resulted in an urgent need for new, clinically useful antibiotics. By 2050, antibiotic resistant micro-organisms are expected to cause more deaths than cancer, road traffic accidents and other chronic diseases worldwide. This is partly because effective antibiotics are essential to prevent infection when carrying out life-saving medical procedures such as surgery and chronic illness management.

Most of the antibiotics used in medicine are produced by actinomycetes, and particularly a genus of non-pathogenic bacteria called Streptomyces, which is abundant in all soil environments.

What are the challenges/needs that this research/initiative addresses?

Based on their genome sequences, each Streptomyces species has the potential to produce on average around 10-15 antibacterial agents of natural product origin. However, when these species are grown under laboratory conditions, only one or two antimicrobial compounds are usually detected. This is because most of these antibiotic gene clusters appear dormant (i.e. are not expressed) under laboratory conditions. The fact Streptomyces species maintain these intact antibiotic gene clusters in their genomes, suggest the products are useful in nature, probably to attack competitor micro-organisms in the harsh soil environment. These dormant or cryptic antibiotic gene clusters represent an untapped resource in terms of novel chemistry, which could lead to new antimicrobial compounds that could be very useful in the clinic.

What findings and solutions were provided by this research/initiative?

For the first time we are culturing two of these Streptomyces species under more ecologically relevant environments such as sterile and non-sterile soils. Next, we aim to understand when previously uncharacterised antibiotic gene clusters encoded within the genomes of these Streptomyces species are expressed and produced in more natural environments. The data generated will provide us with key information which will allow us to generate genetically modified strains, with the ability to produce detectable amounts of these compounds under laboratory and industrial fermentation conditions. 

Why does this research matter?

By understanding the signals which trigger antibiotic production in Streptomyces when grown in soil, we will contribute to alleviating the global AMR challenge in two different ways. On one hand, the results from this research aim to increase the number of novel natural products available to test and, therefore provide many more lead candidates to take forward, in order to produce much needed new clinically relevant antimicrobial compounds. On the other hand, the results will allow us to identify global regulatory pathways which lead to the production of antibiotics in nature. We can then extrapolate those pathways to generate industrial strains that are able to produce antibiotics at much higher yields.

Increasing the yield of production of a compound not only significantly increases its chances of ever making it to the clinic, but also makes the production of that particular drug much more sustainable.

How can this research/initiative support the transition to a more sustainable future?

We hope that our findings will provide tools to increase the much-needed antibiotic pipeline, as well as the yield of both promising novel compounds and existing antibiotics, thus increasing the sustainability of their production at the same time as tackling AMR.

© Lorena Fernández-Martínez
About the author

Dr Lorena Fernández-Martínez is a Reader in Microbial Genetics at Edge Hill University and a member of the Microbiology Society. More information about her work is available here.