Chance and Necessity: Evolution guided antibiotic improvement and discovery

点击翻译按钮获取中文摘要

Streptomyces is a harmless bacterium that is found in soil. Competition for nutrients in soil is intense and it is thought that Streptomyces produce antibiotics to harm competing organisms, such as other bacteria. It is these antibiotics that we exploit in human medicine, where almost two-thirds of our clinically used antibiotics are made naturally by Streptomyces bacteria. The rise in antibiotic resistant infections in recent years has indicated that there is an urgent need for us to discover new antibiotics and increase the production efficiency of existing antibiotics to help us combat the resistance crisis. Understanding how antibiotic producing bacteria regulate the production of antibiotics and what genes are involved in production is important for us to be able to better exploit Streptomyces and their antibiotics in human medicine. When we produce antibiotics at industrial scale, we use Streptomyces bacteria whose DNA has been modified through a process called 'random mutagenesis' - this mutagenesis process creates strains of bacteria that are better adapted to growing in the fermenters and produce more antibiotics that they would naturally. This process essentially accelerates evolution, where scientists select the fittest or best strains for industrial production of antibiotics - but it is time consuming and difficult to direct. Bacteria undergo a similar process to evolve, adapt and survive in their natural soil environment. In this proposal, we wish to study a natural adaptation process in Streptomyces and how its genome adapts to grow in a nutrient rich broth in the laboratory. We also wish to look at the genomes several strains of an industrial Streptomyces species that have been used to make an antibiotic commercially to see how the random mutagenesis process has forced them to adapt to the conditions and make industrial amounts of antibiotic. We hypothesise that the genes acted upon by evolution (either forced or natural) are likely to be similar and as strains adapt, they will lose the activity of genes that are no longer required, such as those for degrading nutrients that they no longer encounter, genes involved in certain stress responses or the ability to form spores. Sequencing the genomes of Streptomyces allows us to look at the genes responsible for the production of antibiotics, and how they have changed during adaptation.If we can understand the mechanisms that drive the adaptation of strains, we will understand what mutations are beneficial and those which are deleterious for surviving in fermenters, adapting to an environment and producing antibiotics. This work will also allow us to understand how different genes interact and if certain combinations of mutations are particularly advantageous or deleterious. This is important because adaptation and the generation of industrial strains is time consuming and labour intensive, but if we understand the order and the kinds of mutations that occur in strains that are high-yielding, then we can rapidly make these mutations in new strains. This will make it easier and quicker to bring new antibiotics to the clinic in the future to combat the growing antimicrobial resistant infection crisis.