Control of <i>gdhR</i> Expression in <i>Neisseria gonorrhoeae</i> via Autoregulation and a Master Repressor (MtrR) of a Drug Efflux Pump Operon

Abstract

The MtrCDE efflux pump of <i>Neisseria gonorrhoeae</i> contributes to gonococcal resistance to a number of antibiotics used previously or currently in treatment of gonorrhea, as well as to host-derived antimicrobials that participate in innate defense. Overexpression of the MtrCDE efflux pump increases gonococcal survival and fitness during experimental lower genital tract infection of female mice. Transcription of <i>mtrCDE</i> can be repressed by the DNA-binding protein MtrR, which also acts as a global regulator of genes involved in important metabolic, physiologic, or regulatory processes. Here, we investigated whether a gene downstream of <i>mtrCDE</i>, previously annotated <i>gdhR</i> in <i>Neisseria meningitidis</i>, is a target for regulation by MtrR. In meningococci, GdhR serves as a regulator of genes involved in glucose catabolism, amino acid transport, and biosynthesis, including <i>gdhA</i>, which encodes an l-glutamate dehydrogenase and is located next to <i>gdhR</i> but is transcriptionally divergent. We report here that in <i>N. gonorrhoeae</i>, expression of <i>gdhR</i> is subject to autoregulation by GdhR and direct repression by MtrR. Importantly, loss of GdhR significantly increased gonococcal fitness compared to a complemented mutant strain during experimental murine infection. Interestingly, loss of GdhR did not influence expression of <i>gdhA</i>, as reported for meningococci. This variance is most likely due to differences in promoter localization and utilization between gonococci and meningococci. We propose that transcriptional control of gonococcal genes through the action of MtrR and GdhR contributes to fitness of <i>N. gonorrhoeae</i> during infection.<b>IMPORTANCE</b> The pathogenic <i>Neisseria</i> species are strict human pathogens that can cause a sexually transmitted infection (<i>N. gonorrhoeae</i>) or meningitis or fulminant septicemia (<i>N. meningitidis</i>). Although they share considerable genetic information, little attention has been directed to comparing transcriptional regulatory systems that modulate expression of their conserved genes. We hypothesized that transcriptional regulatory differences exist between these two pathogens, and we used the <i>gdh</i> locus as a model to test this idea. For this purpose, we studied two conserved genes (<i>gdhR</i> and <i>gdhA</i>) within the locus. Despite general conservation of the <i>gdh</i> locus in gonococci and meningococci, differences exist in noncoding sequences that correspond to promoter elements or potential sites for interacting with DNA-binding proteins, such as GdhR and MtrR. Our results indicate that implications drawn from studying regulation of conserved genes in one pathogen are not necessarily translatable to a genetically related pathogen.