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Evolutionary paths to antibiotic resistance under dynamically sustained drug selection
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Journal Article
Evolutionary paths to antibiotic resistance under dynamically sustained drug selection
2012
Overview
Roy Kishony and colleagues develop a device for the continuous culture of bacterial populations under constant antibiotic selection pressure. They use this morbidostat, together with whole-genome sequencing of
E. coli
strains, to follow evolutionary paths leading to high levels of resistance to three individual drugs.
Antibiotic resistance can evolve through the sequential accumulation of multiple mutations
1
. To study such gradual evolution, we developed a selection device, the 'morbidostat', that continuously monitors bacterial growth and dynamically regulates drug concentrations, such that the evolving population is constantly challenged
2
,
3
,
4
,
5
. We analyzed the evolution of resistance in
Escherichia coli
under selection with single drugs, including chloramphenicol, doxycycline and trimethoprim. Over a period of ∼20 days, resistance levels increased dramatically, with parallel populations showing similar phenotypic trajectories. Whole-genome sequencing of the evolved strains identified mutations both specific to resistance to a particular drug and shared in resistance to multiple drugs. Chloramphenicol and doxycycline resistance evolved smoothly through diverse combinations of mutations in genes involved in translation, transcription and transport
3
. In contrast, trimethoprim resistance evolved in a stepwise manner
1
,
6
, through mutations restricted to the gene encoding the enzyme dihydrofolate reductase (
DHFR
)
7
,
8
. Sequencing of
DHFR
over the time course of the experiment showed that parallel populations evolved similar mutations and acquired them in a similar order
9
.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Analysis
/ Animal Genetics and Genomics
/ Anti-Bacterial Agents - pharmacology
/ Bacteria
/ Biological and medical sciences
/ Biomedical and Life Sciences
/ Drug resistance in microorganisms
/ Drug Resistance, Microbial - genetics
/ E coli
/ Escherichia coli - growth & development
/ Fundamental and applied biological sciences. Psychology
/ Genetics of eukaryotes. Biological and molecular evolution
/ Genomes
/ letter
/ Mutation
