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Inhibitors of bacterial immune systems: discovery, mechanisms and applications

Nature Reviews Genetics volume 25, pages 237–254 (2024)Cite this article

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Abstract

To contend with the diversity and ubiquity of bacteriophages and other mobile genetic elements, bacteria have developed an arsenal of immune defence mechanisms. Bacterial defences include CRISPR–Cas, restriction–modification and a growing list of mechanistically diverse systems, which constitute the bacterial ‘immune system’. As a response, bacteriophages and mobile genetic elements have evolved direct and indirect mechanisms to circumvent or block bacterial defence pathways and ensure successful infection. Recent advances in methodological and computational approaches, as well as the increasing availability of genome sequences, have boosted the discovery of direct inhibitors of bacterial defence systems. In this Review, we discuss methods for the discovery of direct inhibitors, their diverse mechanisms of action and perspectives on their emerging applications in biotechnology and beyond.

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Fig. 1: Bacterial defences against phage invasion and their suppression by phage-encoded inhibitors.
Fig. 2: Approaches used for the discovery of direct inhibitors of bacterial immune systems.
Fig. 3: General mechanisms of defence inhibition by direct inhibitors.
Fig. 4: Biotechnological applications of direct inhibitors.

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Acknowledgements

We thank C. Smart, L. Payne and S. Crellin for helpful discussions. Research on phage defence and anti-defence systems conducted in the Fineran laboratory is supported by a University of Otago Research Grant, Bioprotection Aotearoa and the Marsden Fund, Royal Society of New Zealand (Te Pūtea Rangahau a Marsden, Te Apārangi). D.M.-M. was supported by a University of Otago Doctoral Scholarship and a Postgraduate Publishing Bursary. R.P.-R. was supported by a Lundbeck Foundation grant, MIMOSAS project [R347-2020-2346].

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  1. These authors contributed equally: David Mayo-Muñoz, Rafael Pinilla-Redondo.

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand

    David Mayo-Muñoz, Rafael Pinilla-Redondo, Nils Birkholz & Peter C. Fineran

  2. Genetics Otago, University of Otago, Dunedin, New Zealand

    David Mayo-Muñoz, Nils Birkholz & Peter C. Fineran

  3. Maurice Wilkins Centre for Molecular Biodiscovery, University of Otago, Dunedin, New Zealand

    David Mayo-Muñoz, Nils Birkholz & Peter C. Fineran

  4. Section of Microbiology, University of Copenhagen, Copenhagen, Denmark

    Rafael Pinilla-Redondo & Sarah Camara-Wilpert

  5. Bioprotection Aotearoa, University of Otago, Dunedin, New Zealand

    Nils Birkholz & Peter C. Fineran

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Contributions

D.M.-M., R.P.-R. and N.B. conceptualized the idea. D.M.-M. and R.P.-R. wrote the manuscript with contributions from S.C.-W., N.B. and P.C.F. D.M.-M. prepared Figs. 1 and 4, Table 1 and Box 1. R.P.-R. prepared Table 1 and Box 3. S.C.-W. prepared Fig. 2 and Box 2. N.B. prepared Fig. 3.

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Correspondence to Rafael Pinilla-Redondo or Peter C. Fineran.

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Glossary

Bacteriophages

(Phages). Viruses that infect bacteria.

CRISPR RNAs

Small guide RNAs that assemble with one or multiple Cas proteins and guide them to complementary nucleic acids in invading mobile genetic elements for degradation.

Direct inhibitor

Inhibitory component that specifically targets and interferes with the defence mechanisms that bacteria use to stop mobile genetic element invasion. Direct inhibitors enable mobile genetic elements to overcome host immunity.

Escape mutant

A mobile genetic element that has evolved to evade defence targeting, typically through mutation.

Jumbo phages

Bacteriophages with large genomes, typically over 200 kb.

Mobile genetic element

(MGE). Genetic entity that requires a host cell to propagate and can move within or between cells. Examples include bacteriophages, plasmids and transposons.

Plasmid

Cytoplasmic DNA element that can replicate independently of the bacterial chromosome and can often transfer horizontally to other bacterial cells.

Protospacer adjacent motif

Short DNA sequence (usually 2–6 base pairs in length) that is immediately adjacent to the target sequence of a CRISPR–Cas system. It is essential for differentiating between self and non-self matches during interference.

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Mayo-Muñoz, D., Pinilla-Redondo, R., Camara-Wilpert, S. et al. Inhibitors of bacterial immune systems: discovery, mechanisms and applications. Nat Rev Genet 25, 237–254 (2024). https://doi.org/10.1038/s41576-023-00676-9

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