Selection of Resistant Bacteria at Very Low Antibiotic Concentrations

By E. Gullberg, Sha Cao, O. Berg, Carolina Ilbäck, Linus Sandegren, D. Hughes, D. Andersson. PLoS Pathogens, 2011

1,611 citations recorded by the source corpus.

The widespread use of antibiotics is selecting for a variety of resistance mechanisms that seriously challenge our ability to treat bacterial infections. Resistant bacteria can be selected at the high concentrations of antibiotics used therapeutically, but what role the much lower antibiotic concentrations present in many environments plays in selection remains largely unclear. Here we show using highly sensitive competition experiments that selection of resistant bacteria occurs at extremely low antibiotic concentrations. Thus, for three clinically important antibiotics, drug concentrations up to several hundred-fold below the minimal inhibitory concentration of susceptible bacteria could enrich for resistant bacteria, even when present at a very low initial fraction. We also show that de novo mutants can be selected at sub-MIC concentrations of antibiotics, and we provide a mathematical model predicting how rapidly such mutants would take over in a susceptible population. These results add another dimension to the evolution of resistance and suggest that the low antibiotic concentrations found in many natural environments are important for enrichment and maintenance of resistance in bacterial populations.

Subfields: Genetics, Molecular Medicine, Pollution

View Paper: https://www.semanticscholar.org/paper/50cae1c6f9063606ab32b2df261c2a14a329800a

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Citations in the corpus

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics (2014, background): “Although it is generally assumed that selection of resistant bacteria occurs at antibiotic concentrations between the MIC of the susceptible wild-type population and that of the resistant bacteria, recent studies suggested that such selection could also occur at lower antibiotic concentrations (168)”
Antibiotic Pollution in the Environment: From Microbial Ecology to Public Policy (2019, background): “While de novo resistance evolution in response to anthropogenic selective pressures has received much attention [28,29], recent work has highlighted that antibiotic production in tandem with antibiotic resistance is wide-spread and ancient in microbial ecosystems.”
Review of Antimicrobial Resistance in the Environment and Its Relevance to Environmental Regulators (2016, background): “…the ARG in the context of the host genome and environment (Maher et al., 2012; Roux et al., 2015); relative to the severity and frequency of hazard (Gullberg et al., 2011, 2014); relative to some physical environmental factors, such as temperature (Gifford et al., 2016) and microbial ecology…”
Antibiotic-Resistance Genes in Waste Water. (2017, background): “The concentrations of different compounds that can select for antibiotic resistance are below therapeutic concentrations used in clinical settings [6].”
The Rising Tide of Antimicrobial Resistance in Aquaculture: Sources, Sinks and Solutions (2017, background): “Such material can persist and select for AMR bacteria, even at low concentrations [42], leading to major alterations in the biodiversity of the sediment and water in the near proximity of open aquaculture systems, by replacing susceptible communities of bacteria (and other microorganisms) ”
Antimicrobial use in aquaculture re-examined: its relevance to antimicrobial resistance and to animal and human health. (2013, background): “hibitory concentrations of antimicrobials in the sediment postulated by supporters of this hypothesis would still have sufficient biological activity to affect horizontal gene transfer (HGT) and mutagenesis in bacteria (Beaber et al., 2004; Hastings et al., 2004; Davies, 2009; Gullberg et al., 2011)”
Antimicrobials and Antibiotic-Resistant Bacteria: A Risk to the Environment and to Public Health (2020, background): “It is estimated that the MSC for a diverse range of microorganisms ranges between 1/4 and 1/230 of the MIC values [33,34].”