Ecological and Evolutionary framework for the design of novel bacteriophage therapy products
Lead Research Organisation:
University of Oxford
Department Name: Biology
Abstract
The healthcare system is increasingly under pressure due to the rise of antimicrobial resistance in bacterial pathogens. Multiple call to arms have resulted in a diversification of strategies to mitigate this issue. Human phage therapy is currently a widely advocated "post-antibiotic" approach in which we use the viruses of bacteria, or phages, to clear bacterial infections. It offers multiple advantages,including i) a high targeting specificity, with phages typically infecting only specific strains within a bacterial species, ii) self-dosing through amplification in situ, and iii) co-evolution of the phages with their host, so that if a bacterial strain becomes resistant to aphage, we can find new phage variants that will be able to infect it.
In this proposal, we address two current limitations of phage therapy: the first concerns methods for phage discovery, a task that hasproved challenging in some pathogens. Indeed, isolating virulent phages from the environment to infect specific strains from patients appears at times impossible. We propose here to weaponize the abundant prophages found in bacterial chromosomes using anexperimental evolution approach. The second limitation concerns the combination of phages into cocktails that can be broadly effective to target specific pathogens. For this task, we will implement Biodiversity-Ecosystem functioning strategies to discover design rules for optimized phage combinations. We have chosen to implement our approach on the clinically relevant bacteria: Pseudomonas aeruginosa.
This project will be performed in synergy with a lab that has considerable expertise in evolutionary microbiology and ecology, and where I can bring my own expertise of phage microbiology and large-scale omics data analysis. We believe this topic is timely and of high relevance for the EU and beyond as we work to further unleash the potential of phage therapy for human health and limit the cost of antimicrobial resistance in our societies.
In this proposal, we address two current limitations of phage therapy: the first concerns methods for phage discovery, a task that hasproved challenging in some pathogens. Indeed, isolating virulent phages from the environment to infect specific strains from patients appears at times impossible. We propose here to weaponize the abundant prophages found in bacterial chromosomes using anexperimental evolution approach. The second limitation concerns the combination of phages into cocktails that can be broadly effective to target specific pathogens. For this task, we will implement Biodiversity-Ecosystem functioning strategies to discover design rules for optimized phage combinations. We have chosen to implement our approach on the clinically relevant bacteria: Pseudomonas aeruginosa.
This project will be performed in synergy with a lab that has considerable expertise in evolutionary microbiology and ecology, and where I can bring my own expertise of phage microbiology and large-scale omics data analysis. We believe this topic is timely and of high relevance for the EU and beyond as we work to further unleash the potential of phage therapy for human health and limit the cost of antimicrobial resistance in our societies.
Organisations
Publications
Lindon S
(2024)
Antibiotic resistance alters the ability of Pseudomonas aeruginosa to invade bacteria from the respiratory microbiome
in Evolution Letters
Wolput S
(2024)
Phage-host co-evolution has led to distinct generalized transduction strategies
in Nucleic Acids Research
| Description | Phage therapy has been advocated as a potential solution for the treatment of infections caused by multi-drug resistant bacteria. In this project, we are using a novel approach to isolate virulent phage that can infect antibiotic resistant bacterial cells. Bacteria often carry temperate phage that are integrated into their genomes - in this lifestyle these temperate phage inflict little harm on their bacterial hosts. We have been able to develop novel methods to efficiently induce these temperate phage to transition towards a virulent lifestyle in which they infect and kill their bacterial host cells. These findings suggest that bacteria themselves carry a vast and untapped reservoir of phage that can potentially be modified to make them candidates for phage therapy. At a molecular level, our work is shedding novel insights into the genes that regulate the transition between temperate and virulent lifestyles in phage. |
| Exploitation Route | Phage therapy has been advocated as a potential solution for the treatment of infections caused by multi-drug resistant bacteria. The preliminary findings of this project suggest that it is possible to isolate phage from the genomes of pathogenic bacteria and modify the phage so that they become more harmful to bacterial hosts. These findings will be of broad interest to researchers and clinicians trying to develop phage therapy. |
| Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |