# Structural basis for the extended-spectrum antimicrobial activity of Garvieacin Q

## TL;DR

This study explains how Garvieacin Q, an antimicrobial peptide, can target multiple bacteria by binding to different receptors, offering a way to design better antimicrobials.

## Contribution

The study reveals the structural mechanism enabling GarQ to target multiple species and identifies a novel domain in bacterial receptors.

## Key findings

- GarQ binds to Man-PTS receptors from Lactococcus garvieae and Listeria monocytogenes using conserved and divergent modes.
- A Tudor-like γ+ domain in Lactococcus garvieae sterically restricts access to other bacteriocins, ensuring specificity for GarQ.
- The C-terminal length of GarQ determines pore size and target specificity, offering a design principle for synthetic bacteriocins.

## Abstract

Class IIa and IId bacteriocins are antimicrobial peptides with potential for combating antibiotic-resistant pathogens. However, their species-specific activity, dictated by recognition of the mannose phosphotransferase system (Man-PTS) receptor, often restricts their spectrum. Garvieacin Q/Garvicin Q (GarQ), a newly identified class IId bacteriocin, is unusual in that it targets both Lactococcus garvieae and the non-lactococcal pathogen Listeria monocytogenes, yet the structural basis for this cross-species activity has remained unclear. Using cryo-electron microscopy, we determined the structures of GarQ bound to Man-PTS receptors from Lactococcus garvieae and Listeria monocytogenes. In Lactococcus garvieae, the receptor contains a unique Tudor-like γ+ domain that sterically constrains the N terminus of incoming bacteriocins, thereby enforcing specificity for GarQ while excluding others such as lactococcin A (LcnA). In Listeria monocytogenes, GarQ engages the receptor through the same conserved binding mode, effectively bypassing the unusual species barrier. We further demonstrate that the C-terminal length of GarQ is a critical determinant of pore size and target specificity. Together, these findings uncover the structural mechanism underlying GarQ’s atypical extended-spectrum activity and provide a framework for engineering bacteriocins with customized spectra to combat specific pathogens.

This study establishes a structural basis for how the extended-spectrum bacteriocin Garvieacin Q (GarQ) circumvents the canonical species-specificity of class II bacteriocins by engaging mannose phosphotransferase system receptors from different bacterial genera through both conserved and divergent binding modes. We identify a previously unknown Tudor-like γ+ domain in the Lactococcus garvieae receptor that sterically restricts the access of other bacteriocins, thereby defining bacteriocin specificity. Moreover, we demonstrate that the C-terminal length of GarQ critically determines pore size and bacterial targets, revealing an engineerable principle for designing synthetic bacteriocins with customized spectra against clinically relevant pathogens.