Harnessing Granzyme Pathways: Developing Novel Antimicrobial Therapies Against Resistant Bacterial Strains.

Antimicrobial resistance (AMR) is a critical global health threat, causing over 4.3 million infections annually in OECD countries, with 1.7 million in the EU/EEA. AMR leads to higher mortality, while the economic impact is severe, with increased healthcare costs due to prolonged hospital stays and the need for more expensive treatments, affecting both productivity and societal well-being.MicroGRANZ seeks to explore the antibacterial potential of granzyme proteins—Granzyme A, Granzyme B, and Granzyme M—as novel therapeutic agents to combat antibiotic-resistant bacteria. Granzymes, produced by cytotoxic T lymphocytes and natural killer cells, assist immune cells in pathogen clearance, but also kill extracellular bacteria directly. Granzymes offer great potential as an alternative to antibiotics; however, their mode of action is not well understood.In MicroGRANZ I will employ interdisciplinary approaches including live-cell microscopy and robotic liquid handling, where thousands of bacteria together with host cells can be monitored over time. This will provide a new understanding of granzyme’s specificity for different bacteria, and in combination with immune cells for cell-assisted killing. I will also improve their effectives by combining different granzymes together, also with other host molecules like Granulysin and Perforin, which enable them to get inside cells. Finally, I will use nanomaterials for enhanced and targeted delivery and controlled release into cells.By investigating how granzyme proteins can be used to tackle resistant bacteria, MicroGRANZ aims to develop innovative immunotherapies that address the global challenge of AMR. The outcomes could pave the way for new treatments that strengthen the innate immune response, aligning with international public health priorities and contributing to improved patient outcomes. Ultimately, MicroGRANZ will also make a step change to my career in an interdisciplinary environment of IPPT PAN.