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Nat Commun. 2018 Apr 23;9(1):1599. doi: 10.1038/s41467-018-04059-1.

Evolution of high-level resistance during low-level antibiotic exposure.

Author information

1
Department of Medical Biochemistry and Microbiology, Uppsala University, 75237, Uppsala, Sweden.
2
Department of Cell and Molecular Biology, Uppsala University, 75237, Uppsala, Sweden.
3
Department of Medical Biochemistry and Microbiology, Uppsala University, 75237, Uppsala, Sweden. dan.andersson@imbim.uu.se.

Abstract

It has become increasingly clear that low levels of antibiotics present in many environments can select for resistant bacteria, yet the evolutionary pathways for resistance development during exposure to low amounts of antibiotics remain poorly defined. Here we show that Salmonella enterica exposed to sub-MIC levels of streptomycin evolved high-level resistance via novel mechanisms that are different from those observed during lethal selections. During lethal selection only rpsL mutations are found, whereas at sub-MIC selection resistance is generated by several small-effect resistance mutations that combined confer high-level resistance via three different mechanisms: (i) alteration of the ribosomal RNA target (gidB mutations), (ii) reduction in aminoglycoside uptake (cyoB, nuoG, and trkH mutations), and (iii) induction of the aminoglycoside-modifying enzyme AadA (znuA mutations). These results demonstrate how the strength of the selective pressure influences evolutionary trajectories and that even weak selective pressures can cause evolution of high-level resistance.

PMID:
29686259
PMCID:
PMC5913237
DOI:
10.1038/s41467-018-04059-1
[Indexed for MEDLINE]
Free PMC Article

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