Ecological and Evolutionary framework for the design of novel bacteriophage therapy products

由于细菌病原体中抗菌素耐药性的上升，卫生保健系统面临越来越大的压力。多次呼吁采取行动导致缓解这一问题的战略多样化。人类噬菌体治疗是目前广泛提倡的“后抗生素”方法，我们使用细菌病毒或噬菌体来清除细菌感染。它具有多种优势，包括i)高靶向特异性，噬菌体通常只感染细菌物种中的特定菌株，ii)通过原位扩增自给药，iii)噬菌体与宿主共同进化，因此，如果细菌菌株对噬菌体产生抗性，我们可以找到能够感染它的新的噬菌体变体。在本提案中，我们解决了噬菌体治疗目前的两个局限性：第一个涉及噬菌体发现的方法，这一任务在某些病原体中已被证明具有挑战性。事实上，从环境中分离出有毒性的噬菌体来感染来自患者的特定菌株有时似乎是不可能的。我们在此建议使用实验进化方法将细菌染色体中丰富的噬菌体武器化。第二个限制涉及将噬菌体组合成鸡尾酒，可以广泛有效地针对特定病原体。为此，我们将实施生物多样性-生态系统功能策略来发现优化噬菌体组合的设计规则。我们选择在临床相关的细菌上实施我们的方法：铜绿假单胞菌。这个项目将与一个在进化微生物学和生态学方面有相当专业知识的实验室协同进行，我可以在那里带来我自己在噬菌体微生物学和大规模组学数据分析方面的专业知识。我们认为，在我们努力进一步释放噬菌体治疗对人类健康的潜力并限制我们社会中抗菌素耐药性的成本之际，这一主题对欧盟和其他地区来说是及时和高度相关的。

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.