CpxR-CpxS two-component system exacerbates development of antibiotic resistance in Pseudomonas aeruginosa

Pseudomonas aeruginosa, a member of the ESKAPE pathogens, is notorious for developing multidrug resistance following antibiotic therapy. Overexpression of efflux pumps, often caused by transcriptional factor dysfunction, is a common mechanism behind this resistance. The CpxR-CpxS two-component system has been linked to the expression of the MexAB-OprM efflux pump in P. aeruginosa, but its role in antibiotic resistance development has not been fully understood.

Deleting cpxR, rather than cpxS, significantly reduces multidrug resistant colony formation following sub-lethal antibiotic exposure, indicating that other sensory components or pathways may mediate CpxR activity in antibiotic resistance development. When glucose is used as the sole carbon source, it leads to increased mexA expression and reduced antibiotic susceptibility in the cpxS mutant strain, specifically dependent on cpxR.

GtrS, another EnvZ family sensor kinase, activates CpxR in a cross-talk manner in the absence of CpxS, alongside at least four other sensor kinase genes (envZ, tctE, phoR, and colS). The risk of multiple pathways for antibiotic resistance development in P. aeruginosa clinical isolates is significant, as many OmpR-EnvZ family two-component systems have been implicated in antibiotic resistance.