Off-target gene regulation mediated by transcriptional repressors of antimicrobial efflux pump genes in Neisseria gonorrhoeae.

DNA-binding proteins that control expression of drug efflux pump genes have been termed "local regulators" as their encoding gene is often located adjacent to the gene(s) that they regulate. However, results from recent studies indicate that they can control genes outside efflux pump-encoding loci, which we term as being "off target." For example, the MtrR repressor was initially recognized for its ability to repress transcription of the mtrCDE-encoded efflux pump operon in the strict human pathogen Neisseria gonorrhoeae, but recent results from genetic and microarray studies have shown that it can control expression of nearly 70 genes scattered throughout the chromosome. One of the off-target MtrR-repressed genes is glnA, which encodes glutamine synthetase. Herein, we confirm the capacity of MtrR to repress glnA expression and provide evidence that such repression is due to its ability to negatively influence the binding of a second DNA-binding protein (FarR), which activates glnA. FarR was previously recognized as a transcriptional repressor of the farAB-encoded efflux pump operon. Thus, two DNA-binding proteins previously characterized as repressors of genes encoding efflux pumps that contribute to gonococcal resistance to antimicrobials can act in an opposing manner to modulate expression of a gene involved in basic metabolism.