MtrR Modulates
            <i>rpoH</i>
            Expression and Levels of Antimicrobial Resistance in
            <i>Neisseria gonorrhoeae</i>

Folster, Jason P.; Johnson, Paul J.; Jackson, Lydgia A.; Dhulipali, Vijaya; Dyer, David W.; Shafer, William M.

doi:10.1128/jb.01165-08

Cited by 59 publications

(113 citation statements)

References 33 publications

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“…MtrF is a putative inner membrane protein involved in high-level resistance to hydrophobic agents mediated by the mtrCDE efflux pump (56). MtrF has been proposed either to shuttle antimicrobials to the pump for export or to help stabilize one or more components of the efflux pump (56,57). MtrF and NGO1024 appear to be linked in a regulatory sense, in that the transcripts for these proteins are controlled directly or indirectly by at least four regulatory elements, including NrrF, Fur, and two additional transcriptional repressors, MtrR and MpeR (57,58).…”

Section: Resultsmentioning

confidence: 99%

Control of RNA Stability by NrrF, an Iron-Regulated Small RNA in Neisseria gonorrhoeae

et al. 2013

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bRegulation of gene expression by small noncoding RNAs (sRNAs) plays a critical role in bacterial response to physiological stresses. NrrF, a trans-acting sRNA in Neisseria meningitidis and Neisseria gonorrhoeae, has been shown in the meningococcus to control indirectly, in response to iron (Fe) availability, the transcription of genes encoding subunits of succinate dehydrogenase, a Fe-requiring enzyme. Given that in other organisms, sRNAs target multiple mRNAs to control gene expression, we used a global approach to examine the role of NrrF in controlling gonococcal transcription. Three strains, including N. gonorrhoeae FA1090, an nrrF deletion mutant, and a complemented derivative, were examined using a custom CombiMatrix microarray to assess the role of this sRNA in controlling gene expression in response to Fe availability. In the absence of NrrF, the mRNA halflives for 12 genes under Fe-depleted growth conditions were longer than those in FA1090. The 12 genes controlled by NrrF encoded proteins with biological functions including energy metabolism, oxidative stress, antibiotic resistance, and amino acid synthesis, as well as hypothetical proteins and a regulatory protein whose functions are not fully understood.

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Section: Resultsmentioning

confidence: 99%

Control of RNA Stability by NrrF, an Iron-Regulated Small RNA in Neisseria gonorrhoeae

et al. 2013

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“…The custom Affymetrix GeneChip microarray MPAUTa1520274F has been described previously (23). RNA (10 g) labeling and hybridization were done at the University of Iowa DNA Facility (http://dna-9.int-med.uiowa.edu/) as previously described (23). For each time point and growth condition, hybridizations were done on three separate biological replicates.…”

Section: Methodsmentioning

confidence: 99%

“…Data files generated by GCOS were imported into GeneSpring GX, version 7.3.1 (Agilent Technologies) and were analyzed as described previously (23). Fold change was expressed as the ratio of the expression of an N. gonorrhoeae gene when the organism was grown under iron-depleted conditions to the expression of the same gene when the organism was grown under iron-replete conditions for the 1-, 2-, 3-, or 4-h time point.…”

Section: Methodsmentioning

confidence: 99%

Transcriptional and Functional Analysis of the Neisseria gonorrhoeae Fur Regulon

et al. 2010

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To ensure survival in the host, bacteria have evolved strategies to acquire the essential element iron. In Neisseria gonorrhoeae, the ferric uptake regulator Fur regulates metabolism through transcriptional control of iron-responsive genes by binding conserved Fur box (FB) sequences in promoters during iron-replete growth. Our previous studies showed that Fur also controls the transcription of secondary regulators that may, in turn, control pathways important to pathogenesis, indicating an indirect role for Fur in controlling these downstream genes. To better define the iron-regulated cascade of transcriptional control, we combined three global strategies-temporal transcriptome analysis, genomewide in silico FB prediction, and Fur titration assays (FURTA)-to detect genomic regions able to bind Fur in vivo. The majority of the 300 iron-repressed genes were predicted to be of unknown function, followed by genes involved in iron metabolism, cell communication, and intermediary metabolism. The 107 iron-induced genes encoded hypothetical proteins or energy metabolism functions. We found 28 predicted FBs in FURTA-positive clones in the promoters and within the open reading frames of iron-repressed genes. We found lower levels of conservation at critical thymidine residues involved in Fur binding in the FB sequence logos of FURTA-positive clones with intragenic FBs than in the sequence logos generated from FURTA-positive promoter regions. In electrophoretic mobility shift assay studies, intragenic FBs bound Fur with a lower affinity than intergenic FBs. Our findings further indicate that transcription under iron stress is indirectly controlled by Fur through 12 potential secondary regulators.The acquisition of iron is essential for bacterial pathogenesis. Because iron is insoluble in aqueous environments at neutral pH and has the potential to produce damaging free radicals, the mammalian host tightly sequesters iron (1, 51), lowering the level of free iron available to invading microorganisms to well below what is needed to survive (34). Since survival in the host and hence virulence is dependent on the acquisition of iron, pathogenic bacteria must be able to sense iron availability and globally regulate the transcription of iron acquisition genes. For many gram-positive and gram-negative organisms, including the sexually transmitted disease pathogen Neisseria gonorrhoeae, the crucial balance between acquiring enough iron to grow and avoiding the toxic effects of excess iron is controlled by the ferric uptake regulator (Fur) protein (12, 27, 49). Typically, Fur acts as a transcriptional repressor by binding as a dimer, along with ferrous iron as a corepressor, to regulatory Fur box (FB) sequences in the promoters of iron-regulated genes under iron-rich growth conditions. As intracellular iron stores are depleted, the Fur-Fe 2ϩ dimer dissociates from the promoter, allowing the entry of RNA polymerase and subsequent transcription (22). Fur acts as a global regulator controlling not only the expression of iron acquisition...

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“…In Neisseria, the expression of the general stress response sigma factor RpoH is inhibited by the repressor MtrR, and this subsequently impacts the expression of at least 69 RpoH-regulated genes and the levels of gonococcal susceptibility to H 2 O 2 (868). In C. jejuni, an OmpR-type oxidative stress regulator, CosR, provides overall negative regulation of oxidative stress defense proteins, and its expression is significantly decreased by a superoxide generator, paraquat (914).…”

Section: Bacterial Stress Responsesmentioning

confidence: 99%

“…(A genome-wide microarray analysis revealed ϳ70 genes whose expression can be repressed or activated by MtrR. One of the repressed genes is rpoH, encoding a stress response sigma factor, and as such, inducible MtrR production also increases gonococcal susceptibility to H 2 O 2 [868].) Two AraC family regulators, the MtrA activator and MpeR repressor, also influence MtrCDE expression either directly or indirectly (637,869).…”

Section: Neisseria Efflux Pumpsmentioning

confidence: 99%

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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SUMMARY The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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MtrR Modulates rpoH Expression and Levels of Antimicrobial Resistance in Neisseria gonorrhoeae

Cited by 59 publications

References 33 publications

Control of RNA Stability by NrrF, an Iron-Regulated Small RNA in Neisseria gonorrhoeae

Control of RNA Stability by NrrF, an Iron-Regulated Small RNA in Neisseria gonorrhoeae

Transcriptional and Functional Analysis of the Neisseria gonorrhoeae Fur Regulon

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

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