Engineering Streptomyces bacteria for the sustainable manufacture of antibiotics

工程化链霉菌用于抗生素的可持续生产

• 批准号: BB/Y007611/1
• 负责人: Paul Hoskisson
• 金额: $ 114.16万
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY007611%2F1
• 关键词: Engineering; Streptomyces; bacteria; sustainable; manufacture

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.

链霉菌细菌使抗生素使其能够在环境中生存，而这些分子在临床上用作抗生素，否则，许多现代医学将停止运作。通过使用专业培养基在大型发酵罐中种植链霉菌来实现抗生素的工业生产。所使用的细菌不是野生型链霉菌，而是经过大量“改进”的菌株，以帮助它们有效地产生更多的抗生素。可以将链霉菌的“改进”过程视为植物或动物的选择性育种，在这些植物或动物中，选择了最佳性状的植物或动物。这意味着每一代都更好地适应发酵罐中的生长和人工增长培养基，而不是环境。但是最重​​要的是，它们产生更多的抗生素。这是针对所有工业链霉菌菌株进行的，这是生产商业数量抗生素的漫长而费力的过程。这些发酵中使用的增长媒体（通常称为原料）非常精致，通常昂贵，并且可以与人类和动物营养相互竞争。为了解决英国政府的气候危机，设定了雄心勃勃的零目标，以提高工业流程的可持续性。解决这些目标并提高抗生素生产的可持续性的一种方法是利用废物作为原料。最近，面包废物引起了人们对可持续发酵原料的关注，因为每年数百万吨被食品工业的废物产生。实现这一目标的一个主要局限性是，链霉菌的产生抗生素受到原料中养分的可用性的严格调节，某些营养源导致抑制使抗生素的细胞机械抑制。这意味着某些原料与高水平的生产不兼容，这是其行业采用的障碍。我们认为，通过使用工程生物学原理来合理修改现有高产生的链霉菌菌株，可以解决这个方法。为了进行测试，我们将与GSK合作，GSK制作了一种称为Clavulanic Acid（CA）的重要抗生素，世界卫生组织将其视为其必不可少的药物之一。我们将采用工程设计的设计建造测试 - 学习原理来分析gsks高生产链球菌菌株的基因组，并使用基因组量表建模来确定为什么它们产生大量CA。我们将使用此信息来修改用某些原料，设计遗传回路来限制抗生素产生的机械，并从其他细菌中引入基因，从而使它们能够利用食物浪费的原料而不会损失生产力。然后，我们将在一系列尺度上测试新设计的应变，并与GSK合作，我们将可以使用其工业开发设施来测试生产力。我们认为，这种使用可持续碳源的工程链霉菌方法也将转化为其他工业生产的链霉菌抗生素。这是可能的，因为许多抗生素的构件源于与CA的基础相同的代谢。我们执行该工程生物学任务的方法将使使工业抗生素生产更加可持续变得更加容易，更快。