Project Details
Projekt
How efflux pumping shapes emergent antibiotic resistance in spatially structured multicellular bacterial populations
Applicants
Professorin Dr. Rosalind Allen; Dr. Frank Schreiber
Subject Area
Metabolism, Biochemistry and Genetics of Microorganisms
Microbial Ecology and Applied Microbiology
Microbial Ecology and Applied Microbiology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 503989054
Antimicrobial resistance (AMR) is a major threat to global public health. AMR is a multicellular function that emerges in bacterial populations through evolution; it is closely entwined with cell-to-cell heterogeneity and cell-cell interactions within the complex spatial structure of an infection. Our project focuses on the interplay between two key factors shaping AMR emergence: the ability of bacteria to transport antimicrobials out of the cell via efflux pumps, and their ability to grow as dense, surface-attached biofilms. Both these factors profoundly influence the emergence of AMR; links between these factors are now emerging but their implications for AMR are unclear. We aim to develop a predictive model for the emergence of efflux-driven AMR evolution within spatially structured bacterial multicellular assemblies. In the first funding period, we developed mathematical models for the population-level implications of efflux-mediated cell-cell interactions in dense populations, showed how the morphology of E. coli colony biofilms is strongly affected by efflux, tracked the effects of efflux-mediated interactions in mixed colonies of effluxers and non-effluxers, and identified unusual spatial patterns associated with the evolution of high-level AMR in colonies of efflux overexpressing strains. We also highlighted in a review article emerging evidence on how the evolution of high-level AMR is facilitated and shaped by the interplay between efflux and the biofilm environment. Building on this work, we hypothesize that high-level AMR evolves in biofilms in two stages: first, the emergence of low-level resistant efflux overexpressor mutants is favored by the biofilm environment; second, the combination of efflux activity and the biofilm environment accelerates the emergence of additional mutations that confer high level resistance. In the next funding period, we propose to use E. coli colony biofilms, combined with individual-based computational modelling, to explore this hypothesis. We will first determine whether, and by what mechanisms, the colony biofilm environment favors emergence of mutants with high efflux activity, compared to liquid culture. Next, we will investigate how efflux alters the potential for further resistance evolution within colony biofilms. Finally, we will track experimentally, and in silico, the evolution of high-level AMR within colony biofilms following the initial acquisition of low-level resistance via efflux upregulation. Our project will produce the first quantitative, integrated picture of how the multicellular function of AMR emerges from the interplay between efflux and the biofilm mode-of-growth.
DFG Programme
Priority Programmes
