iProXProteomicsHao LiStreptococcus Gordonii Str. Challis Substr. Ch1http://www.iprox.org/page/project.html?id=IPX0016784000lihao106@shsmu.edu.cnState Key Laboratory of Oral Diseases, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan UniversityiProXfalseCompetence-Driven Metabolism Triggers a Protein Aggregation and ROS Loop to Modulate Bacterial Adaptation to Chemical Cationic BiocidesAntibiotic resistance is a growing concern, yet resistance and cross-resistance to widely used chemical biocides are poorly understood. Here, we show that cationic biocides induce V-type ATPase overactivation in Streptococcus gordonii, shifting metabolism to oxidative phosphorylation and increasing ROS. This triggers protein aggregation (PAs), which amplifies ROS in a lethal feedback loop. Synergistic inactivation of ClpX, a protease ATPase subunit, and PstB, a phosphate transporter component, disrupts the PAs-ROS loop by suppressing the competence regulator ComDE and rewiring metabolism to glycolysis. ClpX inactivation alleviates proteotoxic stress, promoting HtrA-mediated CSP degradation and ComDE downregulation, while PstB dysfunction impairs mannose PTS phosphorylation to further suppress ComDE. Reactivation of ComDE restores biocide susceptibility through the PAs-ROS loop. This mechanism is conserved in other ComDE-encoding streptococci, including Streptococcus pneumoniae, underscoring ComDE-mediated metabolic adaptation as a key regulator of bacterial susceptibility to membrane-targeted and ROS-inducing antimicrobials, and suggesting strategies to mitigate resistance to chemical biocides.Tue Apr 21 00:00:00 BST 2026PXD077459467705