The Ancestral N-Terminal Domain of Big Defensins Drives Bacterially Triggered Assembly into Antimicrobial Nanonets

Type Article
Date 2019-09
Language English
Author(s) Loth Karine1, 2, Vergnes Agnes3, Barreto Cairé3, 4, Voisin Sébastien N5, Meudal Hervé1, Da Silva Jennifer6, Bressan Albert3, 4, Belmadi Nawal6, Bachère Evelyne3, Aucagne Vincent1, Cazevielle Chantal7, Marchandin Hélène8, Rosa Rafael Diego4, Bulet Philippe5, 9, Touqui Lhousseine6, Delmas Agnès F.1, Destoumieux-Garzón Delphine10
Affiliation(s) 1 : Centre de Biophysique Moléculaire UPR4301 CNRS, Orléans, France
2 : UFR CoST, Université d’Orléans, Orléans, France
3 : IHPE, Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, Montpellier, France
4 : Laboratory of Immunology Applied to Aquaculture, Department of Cell Biology, Embryology and Genetics, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
5 : Plateforme BioPark d’Archamps, Archamps Technopole, Archamps, France
6 : Equipe mixte Institut Pasteur/Paris V Mucoviscidose et Bronchopathies Chroniques, Institut Pasteur, Paris, France
7 : COMET, Plateau de microscopie électronique, Plateforme Montpellier RIO Imaging, Montpellier, France
8 : HydroSciences Montpellier, Département de Microbiologie, CHU Nîmes, CNRS, IRD, Université de Montpellier, Nîmes, France
9 : Institute for Advanced Biosciences, CR Université Grenoble Alpes, CNRS UMR5309, La Tronche, France
10 : IHPE, Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, Montpellier, France
Source Mbio (2150-7511) (American Society for Microbiology), 2019-09 , Vol. 10 , N. 5 , P. e01821-19 (15p.)
DOI 10.1128/mBio.01821-19
WOS© Times Cited 20
Keyword(s) MRSA, antimicrobial peptides, antimicrobial resistance, defensins, fibrils, innate immunity, mechanisms of action, nuclear magnetic resonance

Big defensins, ancestors of β-defensins, are composed of a β-defensin-like C-terminal domain and a globular hydrophobic ancestral N-terminal domain. This unique structure is found in a limited number of phylogenetically distant species, including mollusks, ancestral chelicerates, and early-branching cephalochordates, mostly living in marine environments. One puzzling evolutionary issue concerns the advantage for these species of having maintained a hydrophobic domain lost during evolution toward β-defensins. Using native ligation chemistry, we produced the oyster Crassostrea gigas BigDef1 (Cg-BigDef1) and its separate domains. Cg-BigDef1 showed salt-stable and broad-range bactericidal activity, including against multidrug-resistant human clinical isolates of Staphylococcus aureus. We found that the ancestral N-terminal domain confers salt-stable antimicrobial activity to the β-defensin-like domain, which is otherwise inactive. Moreover, upon contact with bacteria, the N-terminal domain drives Cg-BigDef1 assembly into nanonets that entrap and kill bacteria. We speculate that the hydrophobic N-terminal domain of big defensins has been retained in marine phyla to confer salt-stable interactions with bacterial membranes in environments where electrostatic interactions are impaired. Those remarkable properties open the way to future drug developments when physiological salt concentrations inhibit the antimicrobial activity of vertebrate β-defensins.

IMPORTANCE β-Defensins are host defense peptides controlling infections in species ranging from humans to invertebrates. However, the antimicrobial activity of most human β-defensins is impaired at physiological salt concentrations. We explored the properties of big defensins, the β-defensin ancestors, which have been conserved in a number of marine organisms, mainly mollusks. By focusing on a big defensin from oyster (Cg-BigDef1), we showed that the N-terminal domain lost during evolution toward β-defensins confers bactericidal activity to Cg-BigDef1, even at high salt concentrations. Cg-BigDef1 killed multidrug-resistant human clinical isolates of Staphylococcus aureus. Moreover, the ancestral N-terminal domain drove the assembly of the big defensin into nanonets in which bacteria are entrapped and killed. This discovery may explain why the ancestral N-terminal domain has been maintained in diverse marine phyla and creates a new path of discovery to design β-defensin derivatives active at physiological and high salt concentrations.

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Loth Karine, Vergnes Agnes, Barreto Cairé, Voisin Sébastien N, Meudal Hervé, Da Silva Jennifer, Bressan Albert, Belmadi Nawal, Bachère Evelyne, Aucagne Vincent, Cazevielle Chantal, Marchandin Hélène, Rosa Rafael Diego, Bulet Philippe, Touqui Lhousseine, Delmas Agnès F., Destoumieux-Garzón Delphine (2019). The Ancestral N-Terminal Domain of Big Defensins Drives Bacterially Triggered Assembly into Antimicrobial Nanonets. Mbio, 10(5), e01821-19 (15p.). Publisher's official version : , Open Access version :