Using CRISPR/Cas9 genome editing to facilitate antibiotic discovery in novel Streptomyces species

使用 CRISPR/Cas9 基因组编辑促进新链霉菌物种中抗生素的发现

• 批准号: BB/X00967X/1
• 负责人: Rebecca Devine
• 金额: $ 50.5万
• 依托单位: John Innes Centre
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX00967X%2F1
• 关键词: Using; CRISPR; Cas9; genome; editing

Antibiotics are some of our most important medicines; they treat a range of infectious diseases and are also used to prevent infections in immunocompromised patients such as those undergoing chemotherapy or organ transplant surgery. Unfortunately, microorganisms are increasingly developing resistance to our current antibiotics, meaning the antibiotics no longer work as effectively. New antibiotics that have activity against resistant microorganisms are urgently needed. Around two-thirds of currently used antibiotics were developed from compounds made naturally by soil-dwelling bacteria like Streptomyces. Streptomyces are thought to produce many antimicrobial compounds in the environment, but in the lab, they only usually make a few. This means many more antimicrobial molecules remain to be discovered from Streptomyces if we can find ways to switch on these 'silent' pathways in the lab.This project will use genetic engineering to switch on the production of antibiotics in Streptomyces formicae, a new strain isolated from the nests of Tetraponera penzigi plant-ants. S. formicae is a talented strain, with the potential to produce many antimicrobial molecules. So far, only one has been characterised; a new family of antibiotics called the formicamycins which are potent inhibitors of resistant microorganisms. By deleting the genes responsible for formicamycin production, we have shown that S. formicae starts to produce previously 'silent' compounds, including more new antimicrobials that have activity against resistant microorganisms. In this fellowship, I will seek to characterise these new antimicrobials and determine their clinical potential. I also aim to understand how the antimicrobial molecules are made by S. formicae and why deletion of the formicamycin pathway induces the production of these previously silent molecules. By understanding how these silent pathways are switched on, we can determine whether the same approach could be used in the many hundreds of other Streptomyces strains isolated across the globe, facilitating the discovery of many new antimicrobial molecules.

抗生素是我们最重要的药物之一；它们治疗一系列传染病，也用于预防免疫功能低下的患者感染，如接受化疗或器官移植手术的患者。不幸的是，微生物越来越多地对我们现有的抗生素产生耐药性，这意味着抗生素不再有效。迫切需要对耐药微生物具有活性的新型抗生素。目前使用的抗生素中约有三分之二是由生活在土壤中的细菌（如链霉菌）自然产生的化合物开发的。链霉菌被认为能在环境中产生许多抗菌化合物，但在实验室中，它们通常只产生少数几种。这意味着如果我们能在实验室中找到打开这些“沉默”途径的方法，那么从链霉菌中还会发现更多的抗菌分子。该项目将利用基因工程技术启动从penzigi植物的巢穴中分离出的新菌株甲酸链霉菌的抗生素生产。formicae是一种有天赋的菌株，具有产生许多抗菌分子的潜力。到目前为止，只有一种被描述；一种新的抗生素叫做福米卡霉素，它是耐药微生物的有效抑制剂。通过删除负责产生福米卡霉素的基因，我们已经证明，福米卡霉素开始产生以前“沉默”的化合物，包括更多对耐药微生物有活性的新抗菌剂。在这个奖学金，我将寻求表征这些新的抗菌剂和确定其临床潜力。我还旨在了解抗菌分子是如何由formicae产生的，以及为什么删除formicamycin途径会诱导这些先前沉默的分子的产生。通过了解这些沉默途径是如何开启的，我们可以确定同样的方法是否可以用于全球分离的数百种其他链霉菌菌株，从而促进许多新的抗菌分子的发现。