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。他们治疗了一系列感染性疾病，还用于预防免疫功能低下的患者感染，例如接受化学疗法或器官移植手术的患者。不幸的是，微生物越来越多地发展对我们当前的抗生素的抗性，这意味着抗生素不再有效地起作用。迫切需要具有抗性微生物活性的新抗生素。当前使用的抗生素中，大约三分之二是由绿色链霉菌（如链霉菌）自然产生的化合物开发的。链霉菌被认为在环境中产生许多抗菌化合物，但在实验室中，它们通常只生产一些。这意味着，如果我们可以找到可以在实验室中开启这些“无声”途径的方法，那么从链霉菌中仍有更多抗菌分子可以发现。该项目将使用遗传工程来开启型甲链霉菌的抗生素生产，这是一种与Tetraponera Penzigi Plant-plants-ant-tetraptomeics formicae的生产，这是一种新的菌株。 S. formicae是一种才华横溢的菌株，有可能产生许多抗菌分子。到目前为止，只有一个被描述了。一个新的抗生素家族称为甲甲霉素，是抗性微生物的有效抑制剂。通过删除负责甲霉素产生的基因，我们已经表明，甲。甲。链霉菌开始产生先前“静音”化合物，包括更多具有抗抗性微生物活性的新抗菌药物。在这一奖学金中，我将寻求表征这些新的抗菌药物并确定其临床潜力。我还旨在了解抗菌分子是如何通过甲米氏链球菌制成的，以及为什么缺失甲霉素途径会诱导这些先前静默的分子的产生。通过了解如何打开这些静默途径，我们可以确定是否可以在全球分离的许多其他链霉菌菌株中使用相同的方法，从而促进了许多新的抗菌分子的发现。