PHASEK: Phage-Antimicrobial Synergy targeting Escherichia coli and Klebsiella pneumoniae
( PHASEK )

Therapeutics

Research Project: 2025-04-01 - 2028-03-31
Total sum awarded: €1 816 198

Multidrug-resistant (MDR) bacterial infections constitute a major challenge, resulting in significant morbidity and mortality. One of the cornerstones of the management of AMR infections is development of antimicrobials. In recent years several novel antimicrobials have been developed, but the emergence of resistance has already been described, and novel approaches are needed to improve the efficacy of current treatment regimens, while preventing development of resistance. Bacteriophages are viruses that selectively target bacteria, causing lysis of bacterial cells. Phage therapy has emerged as a potential tool to mitigate the effects of AMR. The possibility of using phages in combination with antimicrobials is largely unexplored although our evidence, and that of others, suggests that phages can improve the efficacy of antibiotics. However, there is limited knowledge about how to combine them, how this works in vitro and in vivo including impacts on the immune system. Herein, we describe a project aimed at generating pivotal information on how to optimally combine phages and antimicrobials by using several infection models – in silico, in vitro, ex vivo cell culture, patient-derived organoid models, and murine animal models. We will also investigate the emergence of phage resistance and development of antibodies in animals receiving long-term treatment with phages. This project explores the utility of phage-antimicrobial combinations in various infection models and will direct roadmaps for clinical use.

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  • Martha Clokie, University of Leicester, United Kingdom (Coordinator)
  • Christian Giske, Karolinska Institutet, Sweden (Partner)
  • Li Deng, Helmholtz Zentrum Muenchen - German Research Center for Environmental Health (GmbH), Germany (Partner)
  • Fabrice Pirot, Civils Hospices of Lyon, FRIPHARM, Pharmacy / Université Claude Bernard Lyon 1, France (Partner)
  • Iain Abbott, Monash University, Australia (Partner)
  • Alasdair MacGowan, North Bristol NHS Trust, United Kingdom (Partner)
  • Krystyna Dabrowska, Hirszfeld Institute of Immunology and Experimental Therapy in Wroclaw, Poland (Partner)

The control of bacterial infections is perhaps the most important achievement of modern medicine. However, we have failed to keep pace with microbes becoming increasingly resistant to available antimicrobials. In fact, the increasing isolation of strains resistant to "last resort" antimicrobials has significantly reduced, or in some settings completely removed, the therapeutic options in severe infections. This has sometimes led to fatal outcomes as patients can no longer be treated. Unfortunately, new classes of antimicrobials are rarely invented and antimicrobial resistance continues to spread in an uncontrolled manner. An attractive approach is to combine standard antimicrobials with unconventional therapeutic approaches that can make them more effective. One of the most promising strategies is to use viruses that can selectively infect and kill bacterial cells, and to give these viruses as treatment in combination with antimicrobials. They have the ability to chew through tough cell walls and the slime (or biofilms) that bacteria excrete during infection. We will investigate how to combine bacterial viruses and antimicrobials. We will check to see how they could be used both in lung infections and in bladder infections as both infections can be caused by the same type of bacteria but they grow and cause disease differently. We will explore how phages can be used to clear these infections and identify potential side effects of such treatments, such as development of resistance to or antibodies against the bacterial viruses.

Call

2024 - Interventions moving forward to promote action to counteract the emergence and spread of bacterial and fungal resistance and to improve treatments