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Evolutionary adaptation of bacteria to changing antibiotic environments

Subject Area Evolution, Anthropology
Term from 2014 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 258392688
 
Final Report Year 2025

Final Report Abstract

Antibiotic resistance has become a major threat to global health. New options for treatment of bacterial infections are urgently required. One option is to improve therapy by exploiting our understanding of bacterial evolution, because it is the ability of bacteria for rapid evolution that is at the core of the dramatic spread of resistance. Therefore, this project explored alternative evolutionary hypotheses to improve treatment efficacy using a combination of evolution experiments in the laboratory, whole genome sequence analysis, and functional genetic analysis, all with the model pathogen Pseudomonas aeruginosa. One of the central findings is that the bacterial ability to adapt can be constrained through changing antibiotic environments and thus sequential antibiotic therapy. More specifically, this project demonstrated a high efficacy of sequential therapy if (i) antibiotics are alternated rapidly (e.g., every 12 hours), (ii) antibiotic-induced physiological changes in the bacteria cause disadvantages in the presence of a different, subsequently applied antibiotic (i.e., negative hysteresis), (iii) evolution of resistance to one antibiotic causes increased sensitivity to a second antibiotic due to an evolutionary trade-off (i.e., evolved collateral sensitivity), and/or (iv) antibiotics are included in a sequential protocol towards which resistance evolves with reduced rate. This project revealed that the above principles can improve treatment efficacy of sequential protocols with distinct antibiotics, and, unexpectedly, also antibiotics from the same class and similar mode of action, thereby offering new treatment options that are usually not considered for patient treatment. To substantiate this work, we characterized the molecular mechanisms underlying the effects, involving the cpx envelope stress response system in the case of negative hysteresis and particular efflux pumps in certain cases of collateral sensitivity. We further demonstrated how these phenomena can improve antibiotic combination therapy, how bacteria may overcome collateral sensitivity, how bottlenecks shape bacterial adaptation to antibiotics, how genetically diverse pathogen populations respond to sequential therapy, how widespread and robust negative hysteresis occurs, and we also established the major P. aeruginosa clone type (mPact) strain panel, covering the entire genomic diversity of this species, for in-depth evaluation of the phenomena. Taken together, this project identified several phenomena and conditions that can constrain bacterial adaptation to antibiotic therapy and thereby help the design of new sustainable antibiotic therapy using evolutionary principles.

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