When plasmids meet phages (PlasPhage): Unveiling Mobile Genetic Element conflicts in carbapenem-resistant enterobacteria

Objective

Antimicrobial resistance (AMR) is a global health crisis, with carbapenem-resistant Enterobacterales among the most urgent threats. The epidemiological success of AMR plasmids depends on their interactions with bacterial hosts, yet the factors shaping these associations remain poorly understood. I hypothesize that prophages, ubiquitous integrated viruses of bacteria, are a critical, overlooked force shaping the distribution of AMR plasmids. PlasPhage will determine if prophages act as compatibility factors of critical carbapenem-resistance plasmids by shaping their fitness cost and stability. Focusing on the clinically-relevant pOXA-48 plasmid, this project aims to: 1) map the landscape of prophage-pOXA-48 interactions in clinical Enterobacterales; 2) quantify their impact on plasmid fitness and persistence; 3) elucidate the underlying molecular mechanisms. To address this, I will combine state-of-the-art high-throughput genomics, functional screenings, evolutionary assays, mathematical modelling, and molecular genetics. This will significantly progress the field by: 1) Obtaining the first functional map of the prophage-plasmid interactome in high-risk pathogens; 2) A new predictive framework for plasmid-mediated AMR evolution integrating prophages; 3) Elucidation of key molecular mechanisms of plasmid-prophage cross-talk. By using patient-derived isolates and a non-academic placement in a clinical microbiology setting, PlasPhage ensures translational relevance. Identifying prophage factors that destabilise pOXA-48 plasmids could inspire phage-based therapies that exploit natural conflicts to eliminate AMR plasmids from pathogens. By combining my expertise in phage biology with the host lab’s strength in plasmid biology and the placement’s clinical AMR expertise, this interdisciplinary fellowship will uniquely position me to lead research on the fundamental biology of mobile genetic elements, informing the next generation of anti-AMR strategies.