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Antibiotic resistance and its cost: is it possible to reverse resistance?

Key Points

  • Most antibiotic resistance mechanisms are associated with a fitness cost, which is a key biological parameter that influences the development of resistance.

  • The fitness cost is the main driver of resistance reversibility at the community level. Thus, the bigger the fitness cost, the faster the reversibility.

  • The rate of reversibility is expected to be slow at the community level because of compensatory evolution, cost-free mutations and genetic co-selection.

  • Knowledge about fitness costs and compensatory mutations can be used to reduce the likelihood of bacteria developing resistance, by enabling us to choose antibiotics for which the resistance mechanism confers a high fitness cost and the rate and extent of compensation mutations are low.

  • It may be possible to exploit the detailed knowledge of the physiological basis of fitness costs in the choice and design of novel therapies that could target the physiological weaknesses associated with a particular resistance mechanism.

  • An understanding of fitness costs and compensatory evolution should allow us to make better quantitative predictions about the rate and trajectory of the evolution of resistance to new and old drugs.

Abstract

Most antibiotic resistance mechanisms are associated with a fitness cost that is typically observed as a reduced bacterial growth rate. The magnitude of this cost is the main biological parameter that influences the rate of development of resistance, the stability of the resistance and the rate at which the resistance might decrease if antibiotic use were reduced. These findings suggest that the fitness costs of resistance will allow susceptible bacteria to outcompete resistant bacteria if the selective pressure from antibiotics is reduced. Unfortunately, the available data suggest that the rate of reversibility will be slow at the community level. Here, we review the factors that influence the fitness costs of antibiotic resistance, the ways by which bacteria can reduce these costs and the possibility of exploiting them.

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Figure 1: Mechanisms of resistance acquisition.
Figure 2: Determining fitness of bacterial strains.
Figure 3: Relationship between antibiotic resistance and bacterial fitness.

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Acknowledgements

This work was supported by the Swedish Research Council, the European Union 5th, 6th and 7th Framework Programmes and the Swedish Agency for Innovations Systems (VINNOVA).

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DATABASES

Entrez Genome Project

Caenorhabditis elegans

Campylobacter jejuni

Escherichia coli

Helicobacter pylori

Mycobacterium bovis

Mycobacterium smegmatis

Mycobacterium tuberculosis

Pseudomonas aeruginosa

Salmonella enterica subsp. enterica serovar Typhimurium

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus pyogenes

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Glossary

Fitness

The capability of a genotype or individual to survive and reproduce.

Bypass resistance

The replacement (bypass) of a metabolic step that is normally inhibited by an antibiotic with a new, drug-resistant metabolic enzyme.

Pharmacokinetic properties

Characteristics of a drug that include: its mechanisms of absorption and distribution; the rate at which its action begins and the duration of the effect; the chemical changes of the agent in the body; and the effects and routes of excretion of drug metabolites. Often summarized as what the body does to a drug.

Pharmacodynamic properties

Characteristics of a drug that include: the physiological effects of a drug on the body, on microorganisms or on parasites in or on the body; the mechanisms of drug action; and the relationship between drug concentration and effect. Often summarized as what a drug does to the body.

Selection coefficient

A measure of the fitness of a phenotype relative to wild type (often denoted s), having a value between 0 and 1. When s = 0, there is no fitness reduction, and when s = 1, the mutation is lethal.

Epistasis

An interaction between genes such that the effect of one gene is modified by one or several other genes.

Gene conversion

A recombination event in which one strand of DNA is changed or repaired using information from another strand.

Baseline

Value for the frequency of resistance before the intervention.

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Andersson, D., Hughes, D. Antibiotic resistance and its cost: is it possible to reverse resistance?. Nat Rev Microbiol 8, 260–271 (2010). https://doi.org/10.1038/nrmicro2319

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