Abstract
MtrR is a well-characterized repressor of the Neisseria gonorrhoeae mtrCDE efflux pump operon. However, results from a previous transcriptional profiling study suggested that MtrR also represses or activates expression of at least sixty genes outside of the mtr locus. Evidence that MtrR can directly repress so-called “off target” genes has previously been reported; in particular, MtrR was shown to directly repress glnA, which encodes glutamine synthetase. In contrast, evidence for the ability of MtrR to directly activate expression of gonococcal genes has been lacking; herein, we provide such evidence. We now report that MtrR has the ability to directly activate expression of glnE, which encodes the dual functional adenyltransferase/deadenylase enzyme GlnE that modifies GlnA resulting in regulation of its role in glutamine biosynthesis. With its capacity to repress expression of glnA, the results presented herein emphasize the diverse and often opposing regulatory properties of MtrR that likely contributes to the overall physiology and metabolism of N. gonorrhoeae.
Highlights
A well-established, and often repeated, observation is that mutations that abrogate the DNA-binding ability of these regulators or expression of their respective gene can, depending on the nature of the protein, increase or decrease efflux pump gene expression and levels of bacterial resistance to antimicrobials recognized by the cognate efflux pump [6,7,8,9,10,11,12]
MtrR is a member of the TetR/QacR family of DNA-binding proteins that are known for their capacity to repress bacterial genes encoding drug efflux proteins [2,8,15,16]
Since glnE has been reported to be an essential gene in other pathogens such as Mycobacterium tuberculosis [23,24] and we have been unable to construct a gonococcal glnE null mutant, we posit that the opposing regulatory properties of MtrR on glnA and glnE likely serves to modulate the fidelity of glutamine biosynthesis during infection
Summary
DNA-binding proteins that regulate expression of efflux pump-encoding genes have significance in controlling levels of bacterial resistance to clinically important antibiotics and other antimicrobials [1,2,3,4,5]. Missense mutations that cause radical amino changes (e.g., A39T or G45D) in the helix-turn-helix motif of MtrR significantly decrease its DNA-binding activity resulting in increased expression of mtrCDE and decreased susceptibility of gonococci to hydrophobic drugs, dyes, and detergents [11]. We hypothesize that such regulation (and loss thereof) is important in vivo, as null mutations in mtrR increase fitness of gonococci in vivo when assessed in a female mouse model of lower genital tract infection [17,18]. Since glnE has been reported to be an essential gene in other pathogens such as Mycobacterium tuberculosis [23,24] and we have been unable to construct a gonococcal glnE null mutant (data not presented), we posit that the opposing regulatory properties of MtrR on glnA and glnE likely serves to modulate the fidelity of glutamine biosynthesis during infection
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