A choline-sensing regulator coordinates metabolic adaptation and pathogenesis in Pseudomonas aeruginosa pulmonary infections

Abstract

Pseudomonas aeruginosa exploits host-derived phosphatidylcholine (PC) to establish persistent lung infections, yet the mechanistic link between metabolic adaptation and pathogenesis remains unclear. Here, we demonstrate that choline (Cho)–induced regulator (CodR), a GcvA-type transcriptional regulator, serves as a master regulator integrating virulence, antibiotic resistance, and PC catabolism during pulmonary infection. CodR directly binds Cho, the key metabolite of PC degradation, to activate pchP and norA, facilitating exogenous PC/Cho utilization. Genome-wide profiling reveals that CodR targets conserved motifs in promoters of mexA, pslA, and amrZ, synchronizing virulence and tolerance pathways. codR deletion attenuated biofilm formation, type III secretion system activity, siderophore production, and PC catabolism, reducing bacterial pathogenicity in a murine pneumonia model. Notably, Cho/PC pretreatment potentiates CodR-dependent transcriptional activation of antibiotic resistance genes, elevating tolerance to ciprofloxacin and meropenem. Our findings elucidate a paradigm wherein P. aeruginosa co-opts host-derived Cho via CodR to simultaneously potentiate virulence and antibiotic resilience, exposing CodR as a druggable node to break infection-resistance synergies.