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

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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.