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Synergistic Regulation by ClpX and PstB Modulates Susceptibility to Quaternary Ammonium Compounds in Streptococcus gordonii via Competence-Driven Metabolic Adaptation

ABSTRACT: Overuse of cationic biocides including quaternary ammonium compounds (QACs) poses a growing threat by selecting for antimicrobial resistance. Here, we use Streptococcus gordonii, a commensal opportunistic pathogen, as a model to elucidate the mechanisms of QAC lethality and resistance. We show that QACs trigger V-type ATPase–driven metabolic dysfunction, leading to oxidative phosphorylation (OXPHOS) dominance and excessive reactive oxygen species (ROS) accumulation. Resistance arises through synergistic regulation by ClpX and PstB, which repress the competence pathway regulator ComDE and reprogram metabolism toward aerobic glycolysis, thereby limiting ROS production. Mechanistically, ClpX modulates ComDE signaling through protein aggregation and HtrA-mediated degradation of competence-stimulating peptide, while PstB governs ComDE via phosphorylation of the mannose-specific phosphotransferase system. Activation of ComDE restores ROS-mediated QAC lethality, identifying this pathway as a potential therapeutic target. These findings reveal that metabolic adaptation driven by competence regulon governs biocide susceptibility and adaptation, offering new strategies to counteract QAC resistance and associated cross-resistance in commensal bacteria.

ORGANISM(S): Streptococcus Gordonii Str. Challis Substr. Ch1

SUBMITTER: Biao Ren

PROVIDER: PXD063944 | iProX | Wed May 14 00:00:00 BST 2025

REPOSITORIES: iProX

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