Role of the two-component system AmgRS in early resistance of <i>Pseudomonas aeruginosa</i> to cinnamaldehyde

Exposure of <i>Pseudomonas aeruginosa</i> to cinnamaldehyde (CNA), a natural electrophilic antimicrobial often used as self-medication to treat mild infections, triggers overproduction of the MexAB-OprM efflux system, leading to multidrug resistance. In this study, we demonstrate that CNA exposure induces expression of genes regulated by the two-component system AmgRS. AmgRS activates MexAB-OprM production, independent of repressors MexR and NalD. In addition to the essential role played by the NalC-ArmR pathway in this adaptive process, AmgRS is critical for the survival of <i>P. aeruginosa</i> challenged with CNA. Altogether, these data suggest that efflux-dependent and -independent mechanisms are activated in the early phase of CNA exposure, allowing for progressive enzymatic reduction of the biocide to non-toxic cinnamic alcohol.IMPORTANCEExposure of <i>Pseudomonas aeruginosa</i> to cinnamaldehyde (CNA), an antimicrobial used in self-medication, induces overproduction of the MexAB-OprM efflux system, leading to multidrug resistance. Our study demonstrates that the AmgRS two-component system aids in the survival of <i>P. aeruginosa</i> strain PA14 under CNA exposure through both MexAB-OprM-dependent and -independent mechanisms until the enzymatic reduction of CNA into the less toxic cinnamic alcohol. This discovery highlights the pivotal role of AmgRS in mediating defense against aldehyde biocides, emphasizing its significance in the persistence of <i>P. aeruginosa</i>, a pathogen associated with hospital-acquired infections and cystic fibrosis, and underscores the potential impact on clinical treatment strategies.