Flowering Poration—A Synergistic Multi-Mode Antibacterial Mechanism by a Bacteriocin Fold
Katharine Hammond, Helen Lewis, Samantha Halliwell, Florie Desriac, Brunello Nardone, Jascindra Ravi, Bart W. Hoogenboom, Mathew Upton, Jeremy P. Derrick, Maxim G. Ryadnov
Abstract
Bacteriocins are a distinct family of antimicrobial proteins postulated to porate bacterial membranes. However, direct experimental evidence of pore formation by these proteins is lacking. Here we report a multi-mode poration mechanism induced by four-helix bacteriocins, epidermicin NI01 and aureocin A53. Using a combination of crystallography, spectroscopy, bioassays, and nanoscale imaging, we established that individual two-helix segments of epidermicin retain antibacterial activity but each of these segments adopts a particular poration mode. In the intact protein these segments act synergistically to balance out antibacterial and hemolytic activities. The study sets a precedent of multi-mode membrane disruption advancing the current understanding of structure-activity relationships in pore-forming proteins.