Engineering Streptomyces bacteria for the sustainable manufacture of antibiotics

Streptomyces bacteria make antibiotics to enable them to survive in the environment and it is these molecules that are used clinically as antibiotics, without which, much of modern medicine would cease to function. Industrial production of antibiotics is achieved by growing Streptomyces in large fermenters using specialised media. The bacteria used are not the wild-type Streptomyces, but strains that have undergone extensive rounds of 'improvement' to help them efficiently make more antibiotics. The 'improvement' process for Streptomyces can be thought of like selective breeding of plants or animals, where those exhibiting the best traits are selected for future use. This means that each generation is better adapted for growth and artificial growth media in the fermenter, rather than environment. Yet most importantly they produce more antibiotics. This has been done for all industrial Streptomyces strains and it is a long and laborious process to produce commercial amounts of antibiotic. The growth media (often called feedstocks) used in these fermentations is highly refined, often expensive and can have competing uses with human and animal nutrition.
To address the climate crisis the UK government has set ambitious net zero goals to improve the sustainability of industrial processes. One way to address these targets and to increase the sustainability of antibiotic production is to utilise waste products as feedstocks. Recently bread waste has attracted attention as sustainable fermentation feedstock as millions of tons each year are produced as waste from the food industry. A major limitation to achieving this is that the production of antibiotics by Streptomyces is tightly regulated by availability of nutrients in the feedstock, with certain nutrition sources resulting in the repression of the cellular machinery that makes the antibiotic. This means that some feedstocks are not compatible with high levels of production, acting as a barrier to their adoption by industry.
We believe there is a solution to this, by using the principles of engineering biology to rationally modify existing, high-producing Streptomyces strains. To test this, we will collaborate with GSK, who make an important antibiotic called clavulanic acid (CA), which the World Health Organisation considers as one of its essential medicines. We will employ the design-build-test-learn principles from engineering to analyse the genomes of GSKs high-producing strains of Streptomyces and use genome scale modelling to identify why they produce large amounts of CA. We will use this information to modify the machinery that constrains antibiotic production with certain feedstocks, design genetic circuits and introduce genes from other bacteria that will allow them to utilise feedstocks from food waste without any loss to productivity. We will then experimentally test our newly engineered strains at a range of scales and in collaboration with GSK, we will have access to their industrial development facilities to test productivity. We think that this approach to engineering Streptomyces to utilise sustainable carbon sources will also translate to other industrially produced Streptomyces antibiotics. This is possible because the building blocks for many antibiotics are derived from the same parts of metabolism as the building blocks for CA. Our approach to this engineering biology mission will make it easier and quicker to make industrial antibiotic production more sustainable.

Streptomyces are the industrial workhorses for production of numerous pharmaceutically useful natural products such as antibiotics. Traditionally, feedstocks for industrial fermentations to produce these molecules have had competing uses in human and animal nutrition, such that alternative, sustainable carbon-sources for biotechnology are increasingly sought. The antibiotic strain improvement has been successful at producing high-yielding strains but can take years to yield commercially viable results. This suggests that greater insight into the genomic changes that give rise to increased antibiotic production levels will help in the design of strains able to use sustainable feedstocks. This proposal is focused on using the engineering biology principles of design-build-test-learn to understand the mutations that given rise to high-producing industrial strains using genome scale modelling and a range of 'omics technologies. We will then use this information to modify aspects of metabolism that repress antibiotic production with certain feedstocks and use this to design genetic circuits and introduce genes from other bacteria that will allow them to utilise feedstocks from food waste without any loss to productivity. We will then experimentally test our newly engineered strains in collaboration with GSK at their pilot facilities productivity. We think that this approach to engineering Streptomyces to utilise sustainable carbon sources will also translate to other industrial strains due to similarities in the precursor utilisation and regulation of biosynthesis. We believe our approach to this engineering biology mission will provide easier and quicker routes to sustainable manufacture of antibiotics.