MpeR. In addition to the regulatory action of the DNA binding proteins MtrA and MtrR, a third gonococcal DNA binding protein termed MpeR (Mtr protein efflux regulator) is also involved in the regulation of mtr efflux components. MpeR was first reported by Xxxxxxx and Xxxxxx who searched the FA1090 gonococcal genome for novel putative transcriptional regulators that could serve to regulate the expression of mtrF (62). The repression of mtrF expression by MpeR prompted the investigation of the global impact that MpeR could have as a DNA-binding protein in the gonococcus. MpeR is 35.7kDa in size and is characterized as an AraC-family protein due to sequence similarity of its C- terminal helix-turn-helix motif to that of other AraC-like proteins (62). The first member of the AraC family to be characterized was the AraC protein of E.coli, which regulates the L-arabinose operon (70, 170, 171). Members of the AraC family are found in a wide range of bacterial species and can act as both activators and repressors of transcription. The AraC family of proteins have the capacity to regulate genes with bacterial functions that include sugar catabolism, stress response, and virulence (126). Interestingly, recent microarray studies have demonstrated that expression of mpeR is derepressed under low iron conditions and is regulated by Fur + iron in the gonococcal strain FA19 (53, 90). This lead us to hypothesize that the expression of mpeR could be important for gonococcal pathogenesis in vivo where levels of free iron are limited. Due to the evidence that MpeR is implicated in the regulation of the MtrCDE efflux component MtrF, and the fact that mpeR expression is modulated by the availability of free iron, this body of work sought to determine the role that MpeR plays in the regulation of antimicrobial efflux mechanisms occurring in an iron-dependent mechanism (Figure 2), thus leading to novel insights into gonococcal pathogenesis. As such, the following specific aims listed below will be addressed in this work.
