We have previously shown that the C-type Natriuretic Peptide (CNP), a peptide produced by the lung, prevents Pseudomonas aeruginosa biofilm formation. In the present study, we identified AmiC as the bacterial target explaining CNP effects, and we studied the involvement of the aliphatic amidase AmiE in these effects. Comparison of 3D structures of human natriuretic peptide receptors and Pseudomonas proteins revealed that the bacterial protein AmiC shows significant similarity with the human C-type natriuretic peptide receptor (hNPR-C). Recombinant protein AmiC was purified and protein/peptide interactions assessed using MicroScale Thermophoresis. Results showed that both CNP and hNPR-C agonists bind the AmiC protein. The amiC gene belongs to the ami operon. This operon also encodes the aliphatic amidase AmiE which hydrolyses short-chain aliphatic amides to their corresponding organic acids. We investigated AmiE potential alternative functions in P. aeruginosa. We observed that over expression of AmiE protein altered biofilm formation, bacterial motilities and quorum sensing molecules production. Using several infection models, we demonstrated that AmiE overproduction led to a strong decrease in P. aeruginosa virulence both in vitro and in vivo, suggesting that in addition to its carbon-nitrogen metabolic process activities, AmiE would have multiple other functions. We demonstrate that the bacterial protein AmiC is an ortholog of the eukaryotic receptor hNPR-C, acting as a CNP sensor in P. aeruginosa. Our data show that the whole ami operon has new functions in bacteria, allowing to modulate the switch between chronic and acute infection depending on exposition to host factors.