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Bacterial defences: mechanisms, evolution and antimicrobial resistance

Nature Reviews Microbiology (2023)Cite this article

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Abstract

Throughout their evolutionary history, bacteria have faced diverse threats from other microorganisms, including competing bacteria, bacteriophages and predators. In response to these threats, they have evolved sophisticated defence mechanisms that today also protect bacteria against antibiotics and other therapies. In this Review, we explore the protective strategies of bacteria, including the mechanisms, evolution and clinical implications of these ancient defences. We also review the countermeasures that attackers have evolved to overcome bacterial defences. We argue that understanding how bacteria defend themselves in nature is important for the development of new therapies and for minimizing resistance evolution.

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Fig. 1: Bacteria face diverse threats from competitors, viruses and predators.
Fig. 2: Bacteria have evolved multiple lines of defence against biotic threats.
Fig. 3: Bacteria mount defences in response to diverse cues.
Fig. 4: Bacteria innovate, acquire and accumulate defences.
Fig. 5: Counter-adaptations to bacterial defences by competitors, phages and predators.

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Acknowledgements

The authors thank E. Granato, R. Wheatley, C. Sharp and M. Brockhurst for their helpful comments on the manuscript, and M. Jahn, C. Souque, E. Bakkeren, F. Spragge, J. Palmer, S. Booth, O. Cunrath, C. Maclean and L. Comstock for their literature suggestions. C.D.N. is supported by the Simons Foundation (award number 826672), NSF grant IOS 2017879, and grant RGY0077/2020 from the Human Frontier Science Program. B.R.W. received support from a Gillman Fellowship from the Department of Biological Sciences at Dartmouth. W.P.J.S. and K.R.F. are supported by the NIH (project numbers R01AI093771 and R01AI120633), by European Research Council Grant 787932, and by Wellcome Trust Investigator award 209397/Z/17/Z. W.P.J.S. is also funded by a Sir Henry Wellcome Postdoctoral fellowship award, 222795/Z/21/Z.

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Authors and Affiliations

  1. Division of Genomics, Infection and Evolution, University of Manchester, Manchester, UK

    William P. J. Smith

  2. Department of Biology, University of Oxford, Oxford, UK

    William P. J. Smith & Kevin R. Foster

  3. Department of Biochemistry, University of Oxford, Oxford, UK

    William P. J. Smith & Kevin R. Foster

  4. Department of Biological sciences, Dartmouth College, Hanover, NH, USA

    Benjamin R. Wucher & Carey D. Nadell

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Contributions

W.P.J.S. researched data for article. W.P.J.S., K.R.F., B.R.W. and C.D.N. contributed substantially to the discussion of content. W.P.J.S. and K.R.F. wrote the article. W.P.J.S., B.R.W., C.D.N. and K.R.F. reviewed and edited the manuscript before submission.

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Correspondence to William P. J. Smith or Kevin R. Foster.

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Glossary

Agents

Substances (particularly toxins and injected viral DNA) that, through interaction with targets, produce harm to a bacterial cell.

Bacteriophages

(Phages). Viruses that infect bacteria.

Biofilms

Densely packed cell groups that can contain billions or trillions of cells, enveloped by a secreted extracellular matrix.

Biotherapeutic

Medicine that is derived from (and often incorporating) biological entities. Phages are a potential biotherapeutic for treating bacterial infections.

Collective defence

Any defensive behaviour that becomes more effective when many individuals engage in it. Collective defences benefit the social partners of a focal bacterium, but do not always evolve for this reason.

Competition sensing

The bacterial behaviour of discerning and responding to stress cues associated with competitor activity, often via stress responses. This is often used to regulate defences, especially counter-attacks.

Competitor

Another type of bacterium that competes with a focal bacterium for resources. Often this will be a genetically similar but non-identical bacterium (for example, a different strain), as similar bacteria are most likely to have overlapping resource needs. Genetically identical organisms compete in an ecological sense, but not in an evolutionary sense (as they have the same evolutionary interests). In this Review, we use the term in the former sense.

Counter-attacks

Aggressions in response to aggression (apparent or actual).

Danger sensing

Conceptually similar to competition sensing, but pertaining to cues other than those resulting from direct harm to a focal cell.

Defence mechanisms

Traits that evolved, at least in part, to protect an organism against a threat. This term is often used in the context of bacterial defences against viral threats, but in this Review, we expand it to encompass protection against competitors and predators.

Exploitative competition

Mutually harmful interactions between bacteria, stemming from competition for contested resources (for example, space or nutrients). Contrasts with interference competition, in which harm is inflicted more directly via weaponry or other means.

Horizontal gene transfer

(HGT). The flow of genetic information between two organisms, other than that which occurs via reproduction (vertical gene transfer).

Mutualism

A mutually beneficial evolutionary relationship between two organisms — that is, one in which the fitness of each party is improved by the presence of the other.

Parasitism

An evolutionary relationship between two organisms in which one benefits at the expense of the other. In contrast to predators, parasites are generally smaller than and physically associated with the organisms they exploit.

Plastic responses

Regulated changes to bacterial phenotypes in response to environmental change. Plasticity does not result from genetic change (though it may be genetically encoded).

Pleiotropy

Phenomenon whereby one gene simultaneously affects multiple traits. Through pleiotropy, a defensive adaptation may affect the phenotype of a bacterium in unexpected ways (for example, by reducing its fitness in the absence of a threat).

Preadaptations

Evolutionary adaptations that serve different purposes from the purpose for which they first evolved. For instance, many modern efflux pumps function to remove antibiotics from bacterial cells, but homologous structures probably served different functions (for example, metabolite export) in ancestral strains.

Predators

Organisms that consume others for food, killing them in the process.

Quorum sensing

A widespread density-sensing mechanism found in bacteria and other microbes. Bacteria probe their effective density by secreting small molecules (autoinducers), which stimulate their own production. High autoinducer concentrations then become a proxy for high cell density or for restrictive spatial constraints that limit autoinducer diffusion. Quorum sensing is often used to regulate costly traits the benefits of which depend on collective action.

Stress responses

A set of regulatory pathways found in bacteria that alter gene expression and cell physiology in response to harmful environmental changes and help the bacteria to survive stress.

Stressors

Changes in environmental or physiological conditions that perturb cell homeostasis.

Weaponry

Cellular systems that evolved, at least in part, to harm other organisms.

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Smith, W.P.J., Wucher, B.R., Nadell, C.D. et al. Bacterial defences: mechanisms, evolution and antimicrobial resistance. Nat Rev Microbiol (2023). https://doi.org/10.1038/s41579-023-00877-3

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