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

抗菌素耐药性（AMR）是人类面临的全球最大公共卫生威胁之一，其产生、传播并对医疗、农业、动物食品生产和环境部门造成毁灭性影响。特别是多药耐药菌感染显著增加临床风险。然而，新型抗生素的临床开发渠道十分干燥，而纳米颗粒和单克隆抗体等非传统技术面临着从毒性到高成本的挑战。该项目旨在开发SimCell作为一种高度安全，可定制的新型活性药物，用于治疗细菌AMR。模拟细胞是无染色体细胞，具有设计的遗传电路。本项目创新性地提出了一种通过在SimCell外膜上设计表面展示的纳米体来实现抗原识别和选择性结合目标病原体的策略。这种纳米体-抗原介导的结合有望加强密切和长期的细胞-细胞关联，这将潜在地提高结合到SimCell平台中的接触依赖性杀伤机制的特异性和效率。多种杀伤机制可能协同作用，包括染色体靶向内切酶的共轭转移、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。

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.