Journal
MOLECULAR BIOLOGY AND EVOLUTION
Volume 37, Issue 6, Pages 1637-1646Publisher
OXFORD UNIV PRESS
DOI: 10.1093/molbev/msaa032
Keywords
experimental evolution; mutation supply; ciprofloxacin; Escherichia coli; bottleneck size; antibiotic resistance
Funding
- Vetenskapsradet (the Swedish Research Council) [2017-03593]
- Scandinavian Society for Antimicrobial Chemotherapy [SLS-693211, SLS-876451]
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Experimental evolution is a powerful tool to study genetic trajectories to antibiotic resistance under selection. A confounding factor is that outcomes may be heavily influenced by the choice of experimental parameters. For practical purposes (minimizing culture volumes), most experimental evolution studies with bacteria use transmission bottleneck sizes of 5 x 10(6) cfu. We currently have a poor understanding of how the choice of transmission bottleneck size affects the accumulation of deleterious versus high-fitness mutations when resistance requires multiple mutations, and how this relates outcome to clinical resistance. We addressed this using experimental evolution of resistance to ciprofloxacin in Escherichia coli. Populations were passaged with three different transmission bottlenecks, including single cell (to maximize genetic drift) and bottlenecks spanning the reciprocal of the frequency of drug target mutations (10(8) and 10(10)). The 10(10) bottlenecks selected overwhelmingly mutations in drug target genes, and the resulting genotypes corresponded closely to those found in resistant clinical isolates. In contrast, both the 10(8) and single-cell bottlenecks selected mutations in three different gene classes: 1) drug targets, 2) efflux pump repressors, and 3) transcription-translation genes, including many mutations with low fitness. Accordingly, bottlenecks smaller than the average nucleotide substitution rate significantly altered the experimental outcome away from genotypes observed in resistant clinical isolates. These data could be applied in designing experimental evolution studies to increase their predictive power and to explore the interplay between different environmental conditions, where transmission bottlenecks might vary, and resulting evolutionary trajectories.
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