Development of Sim Cells for Treating Bacterial Antimicrobial Resistance (AMR)

开发用于治疗细菌抗菌素耐药性 (AMR) 的 Sim 细胞

• 批准号: 2600494
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2600494
• 关键词: Development; Sim; Cells; Treating; Bacterial

Antimicrobial resistance (AMR), as one of the top global public health threats facing humanity, emerges from, spreads among and causes devastating effect on medical, agricultural, animal-based-food- producing, also environmental compartments. Especially multidrug-resistant bacteria infections significantly increase the clinical risk. However, clinical pipeline of new antibiotics is dry, while nonconventional technologies such as nanoparticles and monoclonal antibodies face challenges from toxicity to high cost. This project aims at developing SimCell as a highly safe, customizable, and novel live drug for treating bacterial AMR. SimCells are chromosome-free cells with designed genetic circuits. This project innovatively proposes a strategy to enable antigen recognition and selectively binding to target pathogens by engineering surfaced-displayed nanobodies to SimCell outer membrane. This nanobody-antigen mediated binding is expected to enforce close and long-term cell-cell association, which will potentially increase the specificity and efficiency of contact-dependent killing mechanisms incorporated into the SimCell platform. Multi-level killing mechanisms are expected to function cooperatively, including conjugative transfer of a chromosome-targeted endonuclease, delivery of toxic effector proteins, targeted release of molecular drugs and activation of endogenous immune response.

抗菌素耐药性（AMR）是人类面临的全球最大的公共卫生威胁之一，它产生于医疗、农业、动物性食品生产以及环境领域，并在其中传播并对它们造成破坏性影响。尤其是多重耐药细菌感染显着增加临床风险。然而，新型抗生素的临床研发渠道干燥，而纳米颗粒、单克隆抗体等非常规技术面临着毒性和高成本的挑战。该项目旨在将 SimCell 开发为一种高度安全、可定制的新型活体药物，用于治疗细菌 AMR。 SimCell 是具有设计遗传电路的无染色体细胞。该项目创新性地提出了一种策略，通过将表面展示的纳米抗体工程化到 SimCell 外膜上，实现抗原识别并选择性结合目标病原体。这种纳米抗体-抗原介导的结合预计将加强紧密且长期的细胞-细胞关联，这将有可能提高纳入 SimCell 平台的接触依赖性杀伤机制的特异性和效率。多级杀伤机制预计将协同发挥作用，包括染色体靶向核酸内切酶的接合转移、毒性效应蛋白的递送、分子药物的靶向释放和内源性免疫反应的激活。