Evolutionary adaptation of bacteria to changing antibiotic environments

• Applicant: Professor Dr. Hinrich Schulenburg
• Subject Area: Evolution, Anthropology
• Term: from 2014 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258392688

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. During the first funding phase, 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 most important findings is that the ability of bacteria to adapt can be constrained through changing antibiotic environments (i.e., sequential antibiotic therapy), especially 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), and/or (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). During the proposed second funding phase, the obtained results will be used to further address the overarching objective to enhance our understanding of bacterial adaptation to temporally fluctuating antibiotic environments. More specifically, two of the most intriguing results from the first funding phase will be further analysed, in order to obtain a more complete understanding of the discovered phenomena, including (i) negative hysteresis as a key principle to enhance efficacy of sequential therapy and (ii) unexpected high efficacy of sequential treatments with three beta-lactam antibiotics. In the former case, the project will assess the general occurrence of negative hysteresis across different antibiotics, different exact treatment conditions, and also P. aeruginosa genotypes and evaluate to what extent the phenomenon of negative hysteresis has general potential to constrain bacterial evolutionary rates. In the second case, cryopreserved bacteria from the previously performed evolution experiment will be characterized in detail phenotypically in combination with genomics and functional genetics, in order to understand how the alternation of three related antibiotics can constrain bacterial adaptation. Taken together, this project will yield a comprehensive database on the environmental conditions, the selective dynamics, and the involved genetic changes that underlie bacterial adaptation to fluctuating environments. This database may thereby help the design of new sustainable antibiotic therapy that exploits evolutionary knowledge to achieve both eliminating the infectious agent and minimizing resistance spread.

• DFG Programme: Research Grants