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Manufacture Small Molecules, Translational Science

Food For Thought (and Sustainability)

Potato Image: The Marmot from USA, CC BY 2.0, via Wikimedia Commons

Researchers in the UK from the University of Strathclyde, University of Surrey, and GSK have received a grant of £1 million from the Biotechnology and Biological Sciences Research Council (BBSRC) to develop a less carbon-intensive process for manufacturing antimicrobial drugs from bacteria.

The team will use biological engineering to enable food by-products to be used as a feedstock for the bacteria. According to the researchers, there is a need for more sustainable industrial feedstocks for fermentation processes. Their approach will use metabolic modeling to help inform engineering strategies for the development of new bacteria strains for producing antimicrobials. The team also hopes that the process will be translatable to other types of drugs made in Streptomyces bacteria, such as anti-parasitic, anti-cancer, anti-fungal and immunosuppressant drugs – and that it will be a more cost-effective form of production. 

We spoke with two of lead researchers on the project, Paul Hoskisson (Professor and Royal Academy of Engineering Research Chair in Engineering Biology at the University of Strathclyde) and Claudio Avignone Rossa (Professor of Systems Microbiology at the University of Surrey), to learn more. 

How did this work get started?

We’ve known each other for over 20 years, working in the same field – metabolic engineering of Streptomyces bacteria to make antibiotics. We have discussed many aspects of Streptomyces biology over the years, and have both independently collaborated with GSK on different projects. The BBSRC Engineering Biology Mission Award funding call was the perfect opportunity for us to combine our complementary expertise to do some interesting, impactful science with Streptomyces and the GSK team.

What are the biggest challenges involved in developing the right engineering strategy for the bacteria?

Bacteria are viewed as being easy to engineer, but Streptomyces are a very different beast. They are primarily found in soil and are prolific producers of bioactive metabolites that we can exploit as medicines, from antibiotics to immunosuppressives, anti-cancer agents, and anti-parasitics. However, they are less genetically tractable than standard model organisms and are unusual bacteria for a number of reasons. They have large genomes (about twice that of Escherichia coli) and linear chromosomes, and are filamentous and relatively slow growing.

Streptomyces produce bioactive metabolites in response to nutrient limitation, such that they are only produce at specific phases in the lifecycle and are subject to tight regulation in response to nutrient availability via carbon catabolite repression (CCR). To complicate matters further, many industrial strains of Streptomyces have undergone years of empirical strain improvement by untargeted mutagenesis. The nature of these mutations is completely unknown, but each round of mutation is likely to result in changes in metabolism that affect the behaviour of the strain. If we are able to understand this more, we could steer cultures to improved outcomes. 

To use waste streams as feedstocks, we need to first look at how CCR works in Streptomyces, to understand the impact of the strain improving mutations and to augment the natural metabolism to enable use of waste streams without repressing antibiotic production.

What type of food by-product do you hope to use as a feedstock? 

Primarily we will be targeting the large amount of starch that goes to waste from processes such as baking and potato processing – but there are other opportunities to valorize food waste, such as vegetable/plant oils that will reduce competition with human food streams.

Feedstocks are the single largest consumable cost for antibiotic fermentations. Tight regulations around biosynthesis means that highly refined, human food grade feedstock is often used. Alterations to feedstock, or the presence of impurities or toxic by-products, can negatively impact the production of an antibiotic (or other bioactive metabolite), reducing the efficiency of the fermentation process. The industry has been trying to increase sustainability for a number of years by reducing energy consumption, switching to renewables, recycling/recovering solvents in downstream processing, and so on. To date, feedstocks is an area where little progress has been made in the antibiotics industry because of the fastidious nature of production conditions. 

What preliminary work have you completed – and what are the next steps? 

Claudio has been building genome scale models of model strains for a number of years and testing these on different inputs. Paul has been funded by a prestigious Royal Academy of Engineering Research Chair for five years to develop tools and study how empirical strain improvement processes change production strains. Claudio and his team can apply models to the genomic, transcriptomic, and biochemical data that Paul’s team have generated. Together, we can use the tools developed to design new strains and test the hypotheses generated.

GSK have kindly allowed us access to strains, data, and pilot plant facilities to test our work in a bona fide industrial production organism.

The project will run for two years with three dedicated post-doctoral researchers in the University of Strathclyde and University of Surrey. We hope to show that our approach works and also try it in other industrially relevant strains of Streptomyces. We also hope that the approach can be adapted to other microbial genera.

How do you hope this research could contribute to the fight against antimicrobial resistance?

The currently novel antimicrobial pipeline is almost dry. We need new antimicrobial drugs to combat the resistance crisis, but we also need to increase production of existing molecules – and make the process cheaper and more efficient. Our model compound is clavulanic acid, which is on the WHO list of essential medicines. Our approach, through understanding production and using waste streams, should enable cheaper manufacture of clavulanic acid and other essential drugs. We also think it will enable production strains to be developed rationally and much faster than the current “black box” random mutagenesis approach. We will apply the “design-build-test” cycle of engineering biology to try to improve (and ideally, optimize) the process.

There is no lack of antimicrobial drugs waiting to be discovered. However, the development of new antimicrobials is expensive and time consuming. These issues reduce the appetite for tackling the problem. We don’t just need antimicrobials for human use – agricultural and veterinary usage are also important areas and innovation here could perhaps help reduce pressure on existing human drugs. We believe that improved engineering strategies for producing strains could help reduce the discovery-to-profit timeline and make antimicrobials more attractive in commercial drug development.

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