Chance and Necessity: Evolution guided antibiotic improvement and discovery

链霉菌是一种在土壤中发现的无害细菌。土壤中对养分的竞争是激烈的，人们认为链霉菌产生抗生素来伤害竞争生物，如其他细菌。我们在人类医学中使用的正是这些抗生素，临床上使用的抗生素中有近三分之二是由链霉菌自然产生的。近年来抗生素耐药感染的增加表明，我们迫切需要发现新的抗生素，提高现有抗生素的生产效率，以帮助我们对抗耐药性危机。了解产生抗生素的细菌如何调节抗生素的生产以及哪些基因参与了生产，对于我们能够更好地利用链霉菌及其抗生素在人类医学中非常重要。当我们在工业规模上生产抗生素时，我们使用链霉菌，这种细菌的DNA通过一种叫做“随机诱变”的过程进行了修饰——这种诱变过程产生的细菌菌株更适合在发酵罐中生长，并产生比自然情况下更多的抗生素。这一过程本质上加速了进化，科学家在进化过程中选择最适合或最好的菌株用于抗生素的工业生产，但这一过程既耗时又难以指导。细菌在自然土壤环境中进化、适应和生存也经历了类似的过程。在这个提议中，我们希望研究链霉菌的自然适应过程，以及它的基因组如何适应在实验室富含营养的肉汤中生长。我们还希望研究一种工业链霉菌物种的几个菌株的基因组，这些菌株已被用于商业生产抗生素，以了解随机诱变过程如何迫使它们适应条件并生产工业数量的抗生素。我们假设，受进化（无论是被迫的还是自然的）影响的基因很可能是相似的，随着菌株的适应，它们将失去不再需要的基因的活性，例如那些降解它们不再遇到的营养物质的基因，参与某些应激反应的基因或形成孢子的能力。对链霉菌的基因组进行测序可以让我们看到负责产生抗生素的基因，以及它们在适应过程中是如何变化的。如果我们能够了解驱动菌株适应的机制，我们将了解哪些突变对在发酵罐中生存、适应环境和生产抗生素有益，哪些突变有害。这项工作还将使我们了解不同基因如何相互作用，以及某些突变组合是否特别有利或有害。这很重要，因为适应和工业菌株的产生是耗时和劳动密集型的，但如果我们了解高产菌株中发生的突变的顺序和种类，那么我们就可以迅速地在新菌株中产生这些突变。这将使将来更容易和更快地将新抗生素带到诊所，以应对日益严重的抗微生物药物耐药性感染危机。

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.