SafePhage: Engineering synthetic phages with intrinsic biocontainment

全世界抗菌素耐药性水平的上升威胁着我们的卫生保健系统和全球经济，这两者都依赖于廉价和有效的抗菌素药物的现成供应来治疗感染和预防常规护理中发生的感染。噬菌体治疗是传统化学抗生素治疗多药耐药细菌感染的一种有希望的替代方法，已被证明是挽救生命的最后一线治疗。然而，传统的噬菌体疗法在广泛使用和商业化方面面临多重障碍。基于曼彻斯特合成基因组技术的最新进展，一种有希望的新兴替代方案是使用合成噬菌体代替天然噬菌体，这种技术可以从零开始快速设计/构建基因组。合成噬菌体疗法具有许多关键优势，包括但不限于：(1)精确控制噬菌体基因组内容以提高安全性；（ii）目标细菌的可编程特异性，使有益微生物保持完整；（三）将噬菌体导向特定宿主壁龛或细胞类型；（四）添加杀菌毒素，更有效地清除细菌病原体；（五）添加基因或修改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、更有效的治疗方法，并具有更大的能力生产可保护的知识产权，从而为公司提供商业上可行的噬菌体产品。然而，为了发挥这种变革潜力，我们必须首先克服一个主要障碍：防止合成噬菌体在临床之外的不必要释放。在这个项目中，我们专注于开发一项对人类和动物安全使用合成噬菌体疗法至关重要的基础技术：开发用于合成噬菌体的基因组保护技术，以确保其长期生物安全和生物遏制，防止其意外释放和/或被第三方滥用。这种安全机制是所有成熟技术所固有的，在这里，必须对逃逸突变体的进化具有稳健性，同时不会对治疗效果产生负面影响。我们的跨学科项目结合了合成基因组学来设计和构建合成噬菌体，进化微生物学实验来测试不同的生物控制策略如何影响噬菌体逃逸和细菌耐药性进化，以及生物控制如何影响合成噬菌体治疗体外和体内呼吸道感染模型感染的效果。我们相信，基因组保护技术将是整个合成噬菌体技术行业的基础（它远远超出了噬菌体治疗的范围，进入了不同的领域和其他生物技术），对合成噬菌体治疗在全球范围内的广泛商业化和采用至关重要。我们的项目将使英国处于快速增长的全球噬菌体技术产业的前沿，并确保英国在制定安全使用合成噬菌体的全球标准方面发挥主导作用。

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.