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Antibiofilm activity of host defence peptides: complexity provides opportunities

Abstract

Host defence peptides (HDPs) are integral components of innate immunity across all living organisms. These peptides can exert direct antibacterial effects, targeting planktonic cells (referred to as antimicrobial peptides), and exhibit antibiofilm (referred to as antibiofilm peptides), antiviral, antifungal and host-directed immunomodulatory activities. In this Review, we discuss how the complex functional attributes of HDPs provide many opportunities for the development of antimicrobial therapeutics, focusing particularly on their emerging antibiofilm properties. The mechanisms of action of antibiofilm peptides are compared and contrasted with those of antimicrobial peptides. Furthermore, obstacles for the practical translation of candidate peptides into therapeutics and the potential solutions are discussed. Critically, HDPs have the value-added assets of complex functional attributes, particularly antibiofilm and anti-inflammatory activities and their synergy with conventional antibiotics.

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Fig. 1: Diversity of biophysical and structural features of HDPs.
Fig. 2: Proposed mechanisms of action of antibacterial HDPs.
Fig. 3: The biofilm life cycle provides several entry points for the antibiofilm effects of HDPs.

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Acknowledgements

Peptide research in the Hancock laboratory was recently supported by the Canadian Institutes of Health Research (CIHR) (Funding reference no. FDN-154287). M.A.A. is a Vanier and UBC Killam Doctoral Scholar and was supported by a Cystic Fibrosis Canada Studentship (#617081). R.E.W.H. holds a Canada Research Chair and is a UBC Killam Professor.

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The authors contributed equally to all aspects of the article.

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Correspondence to Robert E. W. Hancock.

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E.F.H. and R.E.W.H. have filed patents related to the antibiofilm and immunomodulatory functions of synthetic HDPs. These patents have been assigned to their employer, the University of British Columbia, and licensed to ABT Innovations Inc., in which R.E.W.H. has an ownership position and E.F.H. owns shares. M.A.A. declares no competing interests.

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Nature Reviews Microbiology thanks G. Diamond, P. Stoodley and M. Zasloff for their contribution to the peer review of this work.

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Glossary

Activity landscapes

The chemical spaces of peptides encompass all possible combinations of amino acids for a peptide of length N. The activity landscape can be conceptualized as a topographical map in which a particular function of a host defence peptide (for example, antimicrobial, antibiofilm or immune modulatory) is projected across all possible sequences within the peptide chemical space. In such an illustration, optimal peptide sequences would be represented by peaks, whereas less active peptides would localize within valleys.

Minimal inhibitory concentration

(MIC). The lowest concentration of a compound that prevents visible growth of bacteria. Bacteria are considered susceptible to a compound if the MIC is below the clinical breakpoint for that compound.

Twitching motility

A form of bacterial locomotion that depends on the type IV pilus in the model organism Pseudomonas aeruginosa and contributes to biofilm maturation as well as virulence.

Stringent-stress response

A broadly conserved bacterial stress response that controls adaptation to nutrient deprivation and is activated by a number of different starvation and stress signals. The molecular hallmark of this response is synthesis of the small molecules guanosine tetraphosphate and its precursor, guanosine pentaphosphate.

Abscess

A collection of pus within the tissues that can contain a high density of bacteria. Although not a biofilm per se, it shares several features with biofilms (local infection, can be chronic, high density, guanosine tetraphosphate dependence, adaptive antibiotic resistance or existence of matrix components).

Biofilm matrix

The protective extracellular matrix of a biofilm consisting primarily of bacteria-produced molecules, including polysaccharides, proteins, lipids and extracellular DNA.

Bacteriocin

Peptide toxins produced by bacteria that act upon closely related bacterial strains.

Microcosm

A community, place or situation regarded as encapsulating, in miniature, the characteristic qualities or features of something large.

Air–liquid interface (ALI) models

Cell culture technique in which mammalian cells are grown until they cover a support (for example, a membrane filter) and then the liquid on top of the cells is removed, enabling the growth of organ-like structures (for example, skin).

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Hancock, R.E.W., Alford, M.A. & Haney, E.F. Antibiofilm activity of host defence peptides: complexity provides opportunities. Nat Rev Microbiol (2021). https://doi.org/10.1038/s41579-021-00585-w

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