MtrR. Repression of the mtrCDE efflux system is mediated by the DNA-binding protein MtrR, which was first characterized by Pan and Xxxxxx (151) who cloned the mtrR gene that is 250 base pairs immediately upstream, but divergently transcribed from the mtrCDE operon. Inactivation of mtrR results in increased resistance of gonococci to HAs recognized by the MtrCDE efflux pump (151). MtrR has a mass of 23kDa and belongs to the QacR-TetR family of transcriptional regulators and interacts with DNA by the binding of two homodimers to the promoter of the mtrCDE operon (77, 122). Utilizing a mouse infection model it was shown that loss of the mtrR gene enhances gonococcal fitness in vivo, suggesting that derepression of the MtrCDE efflux pump results in a strain that is better adapted to surviving conditions within the genital tract (206). Derepression of mtrCDE expression can also occur as a result of point mutations in the MtrR binding site, a single-base-pair deletion within a 13bp inverted repeat sequence in the mtrR promoter, or missense mutations in the helix-turn-helix motif of MtrR, all of which result in elevated MtrCDE pump levels of clinical significance in vitro and in vivo (78, 122, 179, 207). Additionally, mutations to the promoter region of mtrR coupled with mutations in both xxxX and penB result in elevated MtrCDE pump levels that render the gonococcus resistant to penicillin (203). Recently it has been reported that mtr120, a C-to- T transition mutation found 120bp upstream of the mtrC start codon, results in a consensus -10 region. This cis-acting mutation generates a novel mtrCDE promoter element that is not subject to either MtrA or MtrR regulation yet results in increased expression of the mtrCDE operon and thus elevated levels of resistance to antimicrobials (Xxxxxx et al. in press). Using microarray analysis, it was found that MtrR can directly or indirectly activate or repress 69 gonococcal genes at different phases of growth including the mtrCDE efflux genes. For example, the gonococcal rpoH gene that encodes the stress response sigma factor RpoH is directly repressed by MtrR, thus linking this transcriptional repressor of a drug efflux operon to survival of gonococci in H202 rich environments (61). Repression of glnA, encoding glutamate synthetase, an enzyme involved in amino acid biosynthesis, is mediated by the ability of MtrR to preclude binding of glnA activator XxxX to the glnA promoter region. Thus, in addition to its role as a repressor o...
