We have performed am important amount of work since the beginning of the project. Over the last 72 months of the project, we have achieved most of the objectives I had proposed, producing high quality results.
We first established the ideas and concepts that we wanted to investigate during PLASREVOLUTION by publishing two perspective/opinion pieces in Trends in Microbiology and Science. In parallel, we started all the experimental work, with the main focus of understanding the evolution of plasmid-mediated antibiotic resistance in the Hospital Universitario Ramon y Cajal, which is a large public hospital in Madrid. Specifically, we have focused our efforts in understanding the evolutionary dynamics of the antibiotic resistance plasmid pOXA-48, which is the an extremely prevalent and relevant carbapenem resistance plasmid worldwide. We have performed an extensive series of epidemiological work, molecular analyses and mathematical modelling to characterize the “in-hospital” ecology and evolution of this plasmid, which we detailed below (work belonging to objectives 1 and 2).
First, we have used mechanistic models combining epidemiological data from more than 9,000 patients with whole genome sequence information from 250 enterobacteria clones to characterise the dissemination routes of a pOXA-48-like carbapenemase-encoding plasmid in our hospital setting over a two-year period. Next, we used these epidemiological and molecular analyses to discover events of in vivo compensatory evolution in the gut of hospitalised patients. Second, we characterized the within-patient evolution of pOXA-48-carrying bacteria. Third, we determined the distribution of fitness effects for the antibiotic resistance plasmid pOXA-48 in wild-type, ecologically compatible enterobacterial isolates from the human gut microbiota. The results of these works have produced five manuscripts (published in Nature Microbiology, Nature ecology and Evolution, Nature Communications, PNAS and Microbiology) . In addition, we have also published a methods paper covering some of the techniques used in these experiments (in Methods in Molecular Biology).
Moreover, we have also experience important progress in objective 3 (plasmid dynamics). Specifically, we uncovered the central role of genetic dominance shaping genetic cargo in plasmids, using antibiotic resistance as a model system. Our results provide a new understanding of how mobile genetic elements evolve and spread, uncovering the neglected influence of genetic dominance on bacterial evolution. As a result, we published a paper on this topic (in PNAS).In addition, we have described that plasmid -encoded ß-lactamases induce collateral sensitivity to other antibiotics in E. coli (paper in eLife and another paper under review in Nature Communications).
In summary, in my opinion the project has been really successful.
