PARADIGM

Antibiotic resistance poses a significant threat to public health, with both clinical and economic consequences. Six pathogens, including Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, are each responsible for over 250,000 deaths annually. Despite ongoing efforts to address this issue, multidrug resistance (MDR) continues to increase. There is a renewed interest in alternative antibacterial treatments, including bacterial viruses called bacteriophages (or phages). Promising results from phage treatments or clinical trials have recently been reported. Phage therapy works best when the phages are tailored to the bacterial strains causing the disease. Therefore, personalized phage therapy requires:
– extensive phage banks to pre-produce phage lots as starting materials
– assays to identify phages effective against the targeted strain
– stable phage products

The PARADIGM project will aim to develop innovative tools and establish a standardized operational workflow for an infrastructure (Phagocenter) that will provide quick access to starting materials for the production of Phage Therapy Medicinal Products (PTMPs) targeting MDR Gram-negative bacteria. This initiative, led by the Assistance Publique-Hôpitaux de Paris (APHP), unites academic research teams from Institut Pasteur (IP), Université Paris Cité (UPC), Sorbonne Université (SU), and the Commissariat à l’Energie Atomique (CEA), who will pave the way for the development of personalized phage therapy in France against multidrug-resistant E. coli, K. pneumoniae, and A. baumannii pathogens. The overarching goal of this project is to establish a national phage biobank and develop cutting-edge in silico and optical tools for faster phagogram analysis. This biobank and analysis workflow will be used by a new APHP infrastructure dedicated to phagotherapy (Phagocenter), ultimately facilitating and accelerating the validation of customized phage cocktails for personalized therapy.
To achieve these goals, the PARADIGM project will implement:
(i) a national biobank for bacterial host cells and phage seed lots
(ii) a quick phage susceptibility workflow combining in silico phagogram and prototypes of innovative systems for rapid imaging of phage-induced lysis
(iii) optical methods to monitor the stability of suspensions of phages in biobanks
(iv) investigate biocompatible chemistries to increase shelf-life of PTMPs.

The project will contribute to the following outcomes:
– Support the creation of a national phage biobank, currently non-existent, for three of the six highest-priority MDR pathogens.
– Develop innovative technologies that enable rapid translation of phage susceptibility assays from research laboratories to hospital settings.
– Contribute to the establishment of national and international standards and processes specific to phage therapy, including the creation of phage biobanks and the implementation of phagograms.
– Foster the development of a French ecosystem for phage therapy research and clinical applications.