SafePhage: Engineering synthetic phages with intrinsic biocontainment

SafePhage：具有内在生物防护的工程合成噬菌体

• 批准号: BB/Y007743/1
• 负责人: Michael Brockhurst
• 金额: $ 220.04万
• 依托单位: University of Manchester
• 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%2FY007743%2F1
• 关键词: SafePhage; Engineering; synthetic; phages; intrinsic

Rising levels of antimicrobial resistance worldwide threaten our healthcare systems and the global economy, which both rely on a ready supply of cheap and effective antimicrobial drugs to treat infections and prevent infections occurring in routine care. Phage therapy is a promising alternative to traditional chemical antibiotics for treating multidrug resistant bacterial infections that has proven to be lifesaving as a last-line treatment. However, conventional phage therapy faces multiple barriers to widespread use and commercialization. A promising emerging alternative is to use synthetic phages in place of natural phages building on recent advances in synthetic genomics technologies in Manchester that enable the rapid design/build of genomes from scratch. Synthetic phage therapy has a number of key advantages, including but not limited to: (i) Precise control over phage genomic contents to improve safety; (ii) Programmable specificity of the targeted bacterium leaving beneficial microbes intact; (iii) Directing phages to specific host niches or cell types; (iv) Adding bacteria-killing toxins to more effectively clear bacterial pathogens; (v) Adding genes or modifications to evade bacterial immunity systems. Synthetic phage therapy, therefore, has the potential to be transformative, offering both safer and more effective treatments for patients, as well as far greater ability to produce protectable IP and thus commercially viable phage-based products for companies. To deliver on this transformative potential, however, we must first overcome a major barrier: preventing unwanted release of synthetic phages outside the clinic. In this project, we focus on developing a foundational technology that will be essential for the safe use of synthetic phage therapy in humans and animals: the development of genome safeguarding technologies for synthetic phages that will ensure their long-term biosecurity and biocontainment, preventing their unintended release and/or misuse by third parties. Such safety mechanisms are inherent to all mature technologies and, here, must be robust to the evolution of escape mutants whilst not negatively impacting treatment effectiveness. Our interdisciplinary project combines synthetic genomics to design and build synthetic phages, evolutionary microbiological experiments to test how different biocontainment strategies affect phage escape and bacterial resistance evolution, together with tests of how biocontainment affects the efficacy of synthetic phage therapy to treat infections in both in vitro and in vivo models of respiratory infection. We believe that genome safeguarding technologies will be foundational for the entire synthetic phage technologies industry (which stretches far beyond phage therapy into diverse fields and other biotechnologies) and will be essential for the widespread commercialization and adoption of synthetic phage therapy worldwide. Our project will place UK at the forefront of the fast-growing global phage-based technologies industry and ensure the UK has a leading role in setting the global standards for safe use of synthetic phages.

全球抗菌素抗性的水平不断上升，威胁着我们的医疗保健系统和全球经济，这两者都依靠准备廉价有效的抗菌药物来治疗感染并防止常规护理中发生感染。噬菌体疗法是​​传统化学抗生素的一种有希望的替代方法，用于治疗多药抗性细菌感染，事实证明是救生作为最后一线治疗的。但是，常规的噬菌体疗法面临广泛使用和商业化的多个障碍。一个有希望的新出现的替代方法是使用合成噬菌体代替曼彻斯特合成基因组技术的最新进步的自然噬菌体，从而使Scratch的基因组快速设计/构建。合成噬菌体疗法具有许多关键优势，包括但不限于：（i）对噬菌体基因组含量的精确控制以提高安全性； （ii）目标细菌的可编程特异性使有益微生物完好无损； （iii）将噬菌体引导到特定的宿主壁ni或细胞类型； （iv）在更有效地清除细菌病原体中添加细菌毒素； （v）添加基因或修饰以逃避细菌免疫系统。因此，合成噬菌体疗法具有变革性的潜力，为患者提供更安全和更有效的治疗方法，以及更大的能力生产可保护的IP，从而为公司提供基于商业上可行的噬菌体产品。但是，要发挥这种变革性的潜力，我们必须首先克服一个主要的障碍：防止诊所外的合成噬菌体的不必要释放。在该项目中，我们专注于开发一种基础技术，该技术对于人类和动物中的合成噬菌体疗法至关重要：开发基因组保护技术用于合成噬菌体，该技术将确保其长期生物安全性和生物植物娱乐，从而防止其意外释放和/或第三方滥用。这种安全机制是所有成熟技术所固有的，在这里，必须对逃生突变体的演变具有鲁棒性，同时不会对治疗有效性产生负面影响。我们的跨学科项目结合了合成基因组学来设计和建立合成噬菌体，进化的微生物学实验，以测试不同的生物内培养策略如何影响噬菌体逃生和细菌抗性的进化，以及生物内疗法如何影响phage phage the Phage the Phage to ant Vivo模型的感染的疗效。我们认为，基因组保护技术将是整个合成噬菌体技术行业的基础（该行业远远超出了噬菌体疗法到各种领域和其他生物技术的范围），对于全球合成噬菌体疗法的广泛商业化和采用。我们的项目将使英国处于基于快速发展的全球噬菌体技术行业的最前沿，并确保英国在确定安全使用合成噬菌体的全球标准方面发挥了领先作用。