MvfR, a key Pseudomonas aeruginosa pathogenicity LTTR‐class regulatory protein, has dual ligands

Abstract

Summary: MvfR (PqsR), a Pseudomonas aeruginosa LysR‐type transcriptional regulator, plays a critical role in the virulence of this pathogen. MvfR modulates the expression of multiple quorum sensing (QS)‐regulated virulence factors; and the expression of the phnAB and pqsA‐E genes that encode functions mediating 4‐hydroxy‐2‐alkylquinolines (HAQs) signalling compounds biosynthesis, including 3,4‐dihydroxy‐2‐heptylquinoline (PQS) and its precursor 4‐hydroxy‐2‐heptylquinoline (HHQ). PQS enhances the in vitro DNA‐binding affinity of MvfR to the pqsA‐E promoter, to suggest it might function as the in vivo MvfR ligand. Here we identify a novel MvfR ligand, as we show that HHQ binds to the MvfR ligand‐binding‐domain and potentiates MvfR binding to the pqsA‐E promoter leading to transcriptional activation of pqsA‐E genes. We show that HHQ is highly produced in vivo, where it is not fully converted into PQS, and demonstrate that it is required for MvfR‐dependent gene expression and pathogenicity; PQS is fully dispensable, as pqsH– mutant cells, which produce HHQ but completely lack PQS, display normal MvfR‐dependent gene expression and virulence. Conversely, PQS is required for full production of pyocyanin. These results uncover a novel biological role for HHQ; and provide novel insights on MvfR activation that may aid in the development of therapies that prevent or treat P. aeruginosa infections in humans.