Key role of an ADP − ribose - dependent transcriptional regulator of NAD metabolism for fitness and virulence of Pseudomonas aeruginosa
Abstract NAD is an essential co-factor of redox reactions and metabolic conversions of NAD-dependent enzymes. NAD biosynthesis in the opportunistic pathogen Pseudomonas aeruginosa has yet not been experimentally explored. The in silico search for orthologs in the P. aeruginosa PAO1 genome identified the operon pncA − pncB1 – nadE (PA4918–PA4920) to encode the nicotinamidase, nicotinate phosporibosyltransferase and Nad synthase of salvage pathway I. The functional role of the preceding genes PA4917 and PA4916 was resolved by the characterization of recombinant protein. PA4917 turned out to encode the nicotinate mononucleotide adenylyltransferase NadD2 and PA4916 was determined to encode the transcriptional repressor NrtR that binds to an intergenic sequence between nadD2 and pncA . Complex formation between the catalytically inactive Nudix protein NrtR and its DNA binding site was suppressed by the antirepressor ADP-ribose. NrtR plasposon mutagenesis abrogated virulence of P. aeruginosa TBCF10839 in a murine acute airway infection model and constrained its metabolite profile. When grown together with other isogenic plasposon mutants, the nrtR knock-out was most compromised in competitive fitness to persist in nutrient-rich medium in vitro or murine airways in vivo . This example demonstrates how tightly metabolism and virulence can be intertwined by key elements of metabolic control. Highlights PA4916-PA4920 encode salvage pathway I of NAD biosynthesis in Pseudomonas aeruginosa . PA4916 encodes the transcriptional repressor NrtR of salvage pathway I. Antirepressor ADP-ribose displaces NrtR from its intergenic binding site. PA4917 encodes the nicotinate mononucleotide adenylyltransferase NadD2. Inactivation of NrtR abrogates virulence and constrains fitness and metabolome. Graphical abstract [DISPLAY OMISSION]
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