Big defensins, ancestors of β-defensins, are composed of a β-defensin-like C-terminal domain and a hydrophobic ancestral N-terminal domain.

This unique structure is found in a limited number of phylogenetically distant species, mostly living in marine environments. Using solid phase peptide chemistry and native chemical ligation, we produced the oyster Crassostrea gigas BigDef1 (Cg-BigDef1) and its separate domains and characterized their 3D structure by NMR. Cg-BigDef1 showed salt-stable and broad-range bactericidal activity, including against multidrug-resistant clinical isolates of S. 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 (ANR MOSAR-Def 2019-2023).

Many thanks to D. Destoumieux-Garzón for collaboration, to “Vaincre La Mucovidose“ and CNRS PEPS X-life” for funding.

Read the article in mBio