Postgraduate research opportunities Chance & Necessity: navigating the strain improvement fitness landscape

Antimicrobial resistance (AMR) is one of the greatest threats to global human health and we need to develop novel approaches to discover new molecules and enhance production of existing molecules. Currently two-thirds of our clinically used antimicrobial drugs are specialised (secondary) metabolites produced by the genus Streptomyces. The traditional process for the development of Streptomyces strains for industrial antibiotic production has been through iterative random mutagenesis followed by the selection of strains with improved production characteristics – this process is undirected and time consuming. The key mutations within these strains, that drive increased industrial performance are often poorly understood and are likely to be the result of cumulative negative effects during multiple rounds of mutation and selection. To address this, we have been using a dual approach to understand evolution of antibiotic production in Streptomyces – a long term evolution experiments of adaptation in Streptomyces and a study of an authentic, industrially improved lineage (forced evolution; FE) of Streptomyces. These studies have shown how adaptation in the LTEE and in the FE results in streamlining of primary metabolism, loss of catabolic breadth and the degradation of competing specialised metabolic pathways. This loss of catabolic capability impacts on growth and yield of antibiotics. Reconditioning of strains with collaterally damaged primary metabolic pathways enabled increased antibiotic titres to be achieved in some industrial strains. Genomics and transcriptomics of evolved strains reveals extensive chromosomal plasticity and transcriptional re-wiring. This project will build on existing studies and attempt to understand the wider role of genetic interactions and how strains may have adapted in culture to enable the process of strain improvement to be accelerated in the future through informed strain engineering.