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2026.02.18.706565v1.full.pdf
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Authors
  • Damoczi, JulienUCLouvain
    Author
  • Pigeolet, LouiseUCLouvain
    Author
  • Cassiers, CélineBiochemistry and Genetics of Microorganisms, Louvain Institute of Biomolecular Science and Technology, Université catholique de Louvain, Louvain-la-Neuve, Belgium
    Author
  • Mignolet, Johannorcid-logoBiochemistry and Genetics of Microorganisms, Louvain Institute of Biomolecular Science and Technology, Université catholique de Louvain, Louvain-la-Neuve, Belgium
    Author
  • Hols, PascalUCLouvain
    Author
Abstract
Bacteria inhabiting competitive microbial environments must rapidly detect and neutralize antimicrobial peptides (AMPs) produced by rivals. The activation of defense pathways relies on dedicated sensors and complex regulatory cascades. Here, we uncover a streamlined, membrane-embedded mechanism in Gram-positive bacteria that directly links detection to transcriptional control. We show that a YtrA-family transcriptional repressor is regulated through an unconventional direct physical interaction with its cognate ABC transporter. In Streptococcus salivarius, the MbrAB efflux pump sequesters the YtrA-like repressor MbrR through a competitive binding mechanism. Upon bacteriocin sensing, MbrR shifts from promoter-proximal DNA repression sites to membrane-associated sequestration via interaction with MbrA, thereby activating the bacteriocin defense system. ATP binding by MbrA facilitates MbrR recruitment, whereas ATP hydrolysis promotes its release, providing a dynamic, flux-responsive feedback loop finely tuned to environmental threat. Structural modeling, synteny, and conservation analyses reveal that this transporter-mediated sequestration mechanism is highly conserved across Gram-positive bacteria, suggesting a widespread and efficient strategy for AMP resistance that bypasses the need for classical sensor kinases. These findings expand the known repertoire of bacterial sensing and resistance systems and provide new insight into how Gram-positive bacteria swiftly adapt to interbacterial antagonism.
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Damoczi, J., Pigeolet, L., Cassiers, C., Mignolet, J., & Hols, P. (2026). A streamlined ABC extruder-repressor module drives multi-bacteriocin resistance in streptococci. BIORXIV. Submitted. https://doi.org/10.64898/2026.02.18.706565 (Original work published 2026)