Regulation of the mexCD-oprJ multidrug efflux operon in Pseudomonas aeruginosa: characterization of the NfxB-EsrC repressor interaction
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The MexCD-OprJ multidrug efflux pump of Pseudomonas aeruginosa is a RND-type efflux system that is capable of exporting, and thus providing resistance to, multiple classes of clinically-relevant antibiotics such as fluoroquinolones, β-lactams and macrolides. Although quiescent in wild-type P. aeruginosa, mexCD-oprJ is induced by membrane-damaging agents such as detergents and the biocide chlorhexidine (CHX), which perturb the cell envelope. Induction of mexCD-oprJ by membrane-damaging agents requires the envelope stress sigma factor AlgU, an indication that MexCD-OprJ is a component of the envelope stress response in P. aeruginosa. In the absence of CHX-mediated envelope stress, the expression of mexCD-oprJ is regulated solely by the NfxB repressor, which binds as a tetramer to the nfxB-mexC intergenic region to repress transcription of the mexCD-oprJ operon. Recently, a second repressor of mexCD-oprJ with homology to NfxB, EsrC, was discovered. In the absence of CHX-mediated envelope stress, the expression of esrC is negatively regulated by NfxB. In the presence of CHX-mediated envelope stress, the repressor activity of NfxB is alleviated and EsrC is produced, where it contributes to moderate repression of the mexCD-oprJ operon, which is expressed at moderate levels. Interestingly, EsrC requires NfxB in order to act as a repressor of the mexCD-oprJ operon. Consistent with previous research, this study demonstrated a physical interaction between NfxB and EsrC. In addition, this study showed that the C-terminal domains of NfxB and EsrC are required for the NfxB-EsrC interaction to occur. The demonstration of an interaction between NfxB and EsrC suggests that these two repressors co-regulate the expression of the mexCD-oprJ operon in the presence of envelope stress to either prevent the potentially detrimental effects of MexCD-OprJ overexpression, or to modulate mexCD-oprJ expression in response to multiple envelope stress signals which are recognized by the NfxB and EsrC components of the heteromultimeric repressor.