PmiR senses 2-methylisocitrate levels to regulate bacterial virulence in Pseudomonas aeruginosa

To adapt to changes in environmental cues, Pseudomonas aeruginosa produces an array of virulence factors to survive the host immune responses during infection. Metabolic products contribute to bacterial virulence; however, only a limited number of these signaling receptors have been explored in detail for their ability to modulate virulence in bacteria. Here, we characterize the metabolic pathway of 2-methylcitrate cycle in P. aeruginosa and unveil that PmiR served as a receptor of 2-methylisocitrate (MIC) to govern bacterial virulence. Crystallographic studies and structural-guided mutagenesis uncovered several residues crucial for PmiR's allosteric activation by MIC. We also demonstrated that PmiR directly repressed the pqs quorum-sensing system and subsequently inhibited pyocyanin production. Moreover, mutation of pmiR reduces bacterial survival in a mouse model of acute pneumonia infection. Collectively, this study identified P. aeruginosa PmiR as an important metabolic sensor for regulating expression of bacterial virulence genes to adapt to the harsh environments.