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  • Review Article
  • Published:

Bacterial gene amplification: implications for the evolution of antibiotic resistance

Nature Reviews Microbiology volume 7, pages 578–588 (2009)Cite this article

Key Points

  • Gene duplication and amplification (GDA) generates genomic variability that is then available for genetic adaptation to altered growth conditions or stresses.

  • GDA constitutes an important adaptive mechanism in bacteria, and resistance to several classes of antibiotic can be conferred by increased gene dosage through GDA. Similarly, the fitness costs of antibiotic resistance can be ameliorated by increased gene dosage of limiting functions.

  • The steady-state frequency of GDA in a population of bacterial cells is high, ranging from 10E−5 to 10E−2, depending on the chromosomal region.

  • GDAs are usually formed and lost at high rates, making them unstable and technically challenging to identify and study.

Abstract

Recent data suggest that, in response to the presence of antibiotics, gene duplication and amplification (GDA) constitutes an important adaptive mechanism in bacteria. For example, resistance to sulphonamide, trimethoprim and β-lactams can be conferred by increased gene dosage through GDA of antibiotic hydrolytic enzymes, target enzymes or efflux pumps. Furthermore, most types of antibiotic resistance mechanism are deleterious in the absence of antibiotics, and these fitness costs can be ameliorated by increased gene dosage of limiting functions. In this Review, we highlight the dynamic properties of gene amplifications and describe how they can facilitate adaptive evolution in response to toxic drugs.

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Figure 1: Bacterial adaptation to antibiotics.
Figure 2: Frequency and response time for point mutations, gene duplication and regulatory responses in a population.
Figure 3: Proposed mechanisms of gene duplication and amplification (GDA).
Figure 4: Gene amplification as a facilitator of antibiotic resistance development.
Figure 5: Amplification of tRNAfMet ameliorates the cost of actinonin resistance mutations.

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Acknowledgements

This work was supported by grants to D.I.A. from the Swedish Research Council and the European Commission 6th Framework Program, and to L.S. from Uppsala University.

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Authors and Affiliations

  1. Department of Medical Biochemistry and Microbiology, Uppsala University, BOX 582, Uppsala, S751 23, Sweden

    Linus Sandegren & Dan I. Andersson

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  1. Linus Sandegren
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Correspondence to Dan I. Andersson.

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DATABASES

Entrez Genome Project

Enterococcus faecalis

Escherichia coli

Proteus mirabilis

Salmonella enterica subsp. enterica serovar Typhimurium LT2

Staphylococcus aureus

Streptococcus agalactiae

Streptococcus pneumoniae

FURTHER INFORMATION

Dan I. Andersson's homepage

Glossary

Bacterial fitness

The ability of the microorganism to survive and generate progeny. Bacterial fitness is often measured by growth rate.

Transduction assays

The study of DNA transfer from one bacterium to another through a bacteriophage in order to assess the duplication frequency of a gene. The transferred DNA contains a selectable marker in the gene of interest.

Non-equal homologous recombination

The exchange of genetic material between repeated regions that are similar or identical, resulting in deletion or duplication and amplification.

Rolling circle replication

Nucleic acid replication that is common in plasmids and bacteriophages and allows rapid synthesis of multiple copies of a genome or specific region.

R plasmid

A plasmid that carries genes that confer antibiotic resistance.

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Sandegren, L., Andersson, D. Bacterial gene amplification: implications for the evolution of antibiotic resistance. Nat Rev Microbiol 7, 578–588 (2009). https://doi.org/10.1038/nrmicro2174

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