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Research GELIFES

GELIFES Seminars - Tobias Bollenbach

When:Th 27-06-2019 16:00 - 17:00
Where:5172.0571

Tobias Bollenbach (University of Cologne)

Perturbing the evolvability of antibiotic resistance

To mitigate the looming antibiotic resistance crisis, new approaches for slowing down resistance evolution are urgently needed. Resistance often emerges due to spontaneous mutations and, consequently, changes in mutation rate affect the evolvability of resistance. However, the role of other cellular mechanisms in evolutionary adaptation to drugs is poorly understood. I will present a systematic approach to identify cellular pathways that directly affect the evolvability of resistance. Using a novel robotic lab-evolution platform that dynamically adjusts drug concentrations for hundreds of parallel Escherichia coli populations, we quantified the effects of a genome-wide selection of pre-existing gene deletions on resistance evolution. Initial resistance of deletion strains differed by more than tenfold but converged toward a hard upper bound for resistance during the evolution experiment, reflecting a global pattern of diminishing returns epistasis. We identified specific cellular functions that drastically curtail the evolvability of resistance; beyond DNA repair, these include membrane transport, LPS biosynthesis, and chaperones. Perturbations of efflux pumps prevented resistance evolution completely or forced evolution on inferior mutational paths, not explored in the wild type. We show that strong negative epistasis generally underlies these phenomena. The identified pathways provide new targets for adjuvants tailored to block evolutionary paths to resistance when combined with antibiotics.