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  • Review Article
  • Published:

Microbiological effects of sublethal levels of antibiotics

Key Points

  • Bacteria are often exposed to non-lethal (that is, subinhibitory) levels of antibiotics in humans, animals and the environment.

  • Subinhibitory levels of antibiotics accelerate the emergence and spread of antibiotic-resistant bacteria by selecting for resistance, generating genotypic and phenotypic variability and functioning as signalling molecules.

  • Subinhibitory levels of antibiotics that are several hundred-fold below the minimal inhibitory concentration (MIC) can select for resistant bacteria.

  • Subinhibitory levels of antibiotics can promote genetic variability by increasing rates of mutation, recombination and horizontal gene transfer.

  • Antibiotics at subinhibitory concentrations can function as signalling molecules and cause alterations in bacterial virulence, biofilm formation, quorum sensing, gene expression and gene transfer. These changes may influence susceptibility to antibiotics.

Abstract

The widespread use of antibiotics results in the generation of antibiotic concentration gradients in humans, livestock and the environment. Thus, bacteria are frequently exposed to non-lethal (that is, subinhibitory) concentrations of drugs, and recent evidence suggests that this is likely to have an important role in the evolution of antibiotic resistance. In this Review, we discuss the ecology of antibiotics and the ability of subinhibitory concentrations to select for bacterial resistance. We also consider the effects of low-level drug exposure on bacterial physiology, including the generation of genetic and phenotypic variability, as well as the ability of antibiotics to function as signalling molecules. Together, these effects accelerate the emergence and spread of antibiotic-resistant bacteria among humans and animals.

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Figure 1: Ecology of antibiotics and antibiotic resistance.
Figure 2: Influence of sub-MIC levels of antibiotics on HGT, recombination and mutagenesis.

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Acknowledgements

D.I.A. and D.H. are supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, the Swedish Governmental Agency for Innovation Systems, the Knut and Alice Wallenberg Foundation, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) (to D.I.A), and the European Union Seventh framework program EvoTAR project (to D.I.A.).

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Glossary

Minimal inhibitory concentration

(MIC). The lowest concentration of an antibiotic that, under a defined set of experimental conditions, inhibits visible growth of a bacterial culture.

Antibiotic gradients

The gradual increases or decreases in antibiotic concentration that are observed between two spatially segregated sites (for example, two tissues in the body).

Aquaculture

The farming of aquatic organisms such as fish, mollusks and aquatic plants.

Minimal selective concentration

(MSC). The lowest concentration of an antibiotic that results in the selection of a resistant mutant in a population over an isogenic susceptible strain.

Mutational space

All possible mutations that can confer a specific phenotype. This can vary from one to several mutations, depending on the system that is studied.

FACS

(Fluorescence-activated cell sorting). A laser-based technology that is used for cell sorting and cell counting, in which fluorescently tagged suspended cells pass through an electronic detection apparatus.

Periodic selection

A type of natural selection in which diversity within a bacterial population is recurrently purged owing to the emergence of adaptive mutants that outcompete other bacteria in the population.

Selection coefficient

A measure of the relative fitness of a strain or phenotype (it can also be used to refer to selective differences between genotypes).

Fitness cost

In the context of this review, the reduction in growth and reproductive potential that accompanies a resistance mutation or other genetic change.

Mutator bacteria

Bacteria with increased mutation rates; they are typically the result of inactivating mutations in DNA repair systems (such as the mismatch-repair system).

SOS response

A global response to DNA damage in which cell growth is arrested and DNA repair and mutagenesis are induced. The key proteins that are involved are RecA and LexA.

Integrative conjugative elements

(ICEs). Mobile genetic elements in bacterial chromosomes; they have the ability to be transferred between cells by conjugation. They encode the integrative ability of bacteriophages and transposons and the transfer mechanism of conjugative plasmids.

RecBCD pathway

A pathway of homologous recombination that utilizes the enzyme complex RecBCD and targets DNA with double-strand breaks. It requires RecA for strand invasion.

RecFOR pathway

A pathway of homologous recombination that involves the enzymes RecJ and RecFOR. It primarily functions on DNA with single-strand breaks and requires RecA for strand invasion.

Mismatch-repair system

A strand-specific DNA-repair system that is present in most organisms; it recognizes and repairs erroneous DNA replication and recombination and DNA damage.

Sigma factors

Transcription factors that target RNA polymerase to specific gene promoters during the initiation of transcription.

Secondary metabolites

Organic compounds that are not directly involved in the normal growth, development and reproduction of an organism.

Competence

A transient physiological state in which bacteria are proficient in the uptake of extracellular DNA. Natural competence is usually regulated in response to environmental signals.

Exoprotein

An extracellular protein. Examples include haemolysin, nuclease and protease, which are exported by Staphylococcus aureus and are involved in the lysis of eukaryotic host cells.

Biocides

Toxic chemicals (or sometimes organisms) that have an inhibitory effect on a living organism (such as a bacterium).

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Andersson, D., Hughes, D. Microbiological effects of sublethal levels of antibiotics. Nat Rev Microbiol 12, 465–478 (2014). https://doi.org/10.1038/nrmicro3270

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