Control of gdhR expression in Neisseria gonorrhoeae via autoregulation and a master repressor (MtrR) of a drug efflux pump operon

The Mtr CDE efflux pump of Neisseria gonorrhoeae contributes to gonococcalresistance to a number of antibiotics used previously or currently in treatmentof gonorrhea, as well as to host-derived antimicrobials that participate in innatedefense. Overexpression of the Mtr CDE efflux pump increases gonococcal survival and fitness during experimental lower genital tract infection of female mice. Transcription of mtr CDE can be repressed by the DNA-binding protein Mtr R, whichalso acts as a global regulator of genes involved in important metabolic, physiologic, or regulatory processes. Here, we investigated whether a gene downstream ofmtr CDE, previously annotated gdh R in Neisseria meningitidis, is a target for regulationby Mtr R. In meningococci, Gdh R serves as a regulator of genes involved in glucosecatabolism, amino acid transport, and biosynthesis, including gdh A, which encodesan L-glutamate dehydrogenase and is located next to gdh R but is transcriptionallydivergent. We report here that in N. gonorrhoeae, expression of gdh R is subject toautoregulation by Gdh R and direct repression by Mtr R. Importantly, loss of Gdh R significantlyincreased gonococcal fitness compared to a complemented mutant strainduring experimental murine infection. Interestingly, loss of Gdh R did not influenceexpression of gdh A, as reported for meningococci. This variance is most likely due todifferences in promoter localization and utilization between gonococci and meningococci. We propose that transcriptional control of gonococcal genes through theaction of Mtr R and Gdh R contributes to fitness of N. gonorrhoeae during infection. IMPORTANCE The pathogenic Neisseria species are strict human pathogens thatcan cause a sexually transmitted infection (N. gonorrhoeae) or meningitis or fulminantsepticemia (N. meningitidis). Although they share considerable genetic information, little attention has been directed to comparing transcriptional regulatory systemsthat modulate expression of their conserved genes. We hypothesized thattranscriptional regulatory differences exist between these two pathogens, and weused the gdh locus as a model to test this idea. For this purpose, we studied twoconserved genes (gdh R and gdh A) within the locus. Despite general conservation ofthe gdh locus in gonococci and meningococci, differences exist in noncoding sequencesthat correspond to promoter elements or potential sites for interacting with DNA-binding proteins, such as Gdh R and Mtr R. Our results indicate that implications drawn from studying regulation of conserved genes in one pathogen are not necessarily translatable to a genetically related pathogen.