Understanding therapeutic phages

Summary

Antibiotic resistance is becoming a greater problem in today’s society, leading to previously treatable infections becoming more dangerous. It is therefore important that the development of new treatment options is pursued. There are different strategies being investigated for this, but a major area of interest is the use of bacteriophages. Bacteriophages (phages) are small viruses which specifically target bacteria. They bind to the bacterium and reproduce inside it. This process results in bacterial death as new phage are released. These phages can then further attack the bacterial population. This makes bacteriophages an interesting and potentially very safe therapeutic option due to their specificity towards bacteria, killing capacity and ability to self-amplify. One pathogen for which phage therapy can be particularly useful is Pseudomonas aeruginosa. In this thesis, we have investigated factors influencing the efficacy of therapeutic phages against this pathogen. First of all, we have developed and validated an assay to monitor phage activity against Gram negative bacteria in real time. Using this assay, we have evaluated the activity of phages in human serum. Here, we found that the complement system, an important agent of the innate immune system, can recognize and inhibit phages of a certain type, potentially compromising their antibacterial activity. Next, we studied how phages can work together with antibiotics of certain classes to eliminate P. aeruginosa. Our results showed that phages can act in a synergistic way with several different antibiotics, particularly the beta lactams meropenem and ceftazidime. Finally, we dove into the mechanisms of bacterial defense and resistance against phages, in a review that also discusses the clinical implications of these mechanisms. Taken together, the work of this thesis has provided new tools to study phage-bacteria interactions. Furthermore, we have generated knowledge about how therapeutic phages may be influenced by factors like the human immune system and antibiotic co-treatments. One of the main general conclusions we can draw from this research is that it is crucial to choose the optimal phages to maximize the chances of therapeutic success. Currently, phages are chosen for therapy mainly based on whether they can infect a given pathogenic strain. We think that it would be very beneficial to take other factors into account, like how the patient’s immune system will affect them, what antibiotics are administered at the same time, and how resistance to these phages can develop. By expanding our knowledge on these topics, we hope to eventually be able to predict which phages are the most suited for each individual patient, thereby contributing to the design of better phage therapy strategies.

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