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

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.