Determining the Relative Contribution and Hierarchy of hha and qseBC in the Regulation of Flagellar Motility of Escherichia coli O157:H7

Sharma, Vijay Kumar; Casey, Thomas A.

doi:10.1371/journal.pone.0085866

Cited by 10 publications

(12 citation statements)

References 58 publications

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“…Using a chemically synthesized fluorescent indole probe, we obtained evidence to support that indole could bind to the sensor protein Le-QseC in L. enzymogenes. The QseC/QseB signaling system is very important for the virulence and motility of enterohemorrhagic E. coli, which uses epinephrine/norepinephrine and AI-3 as signal molecules (35)(36)(37)(38)(39)(40). However, the nature of this so-called AI-3 remains unclear, other than that AI-3 was suggested to be a group of bacterial aromatic compounds.…”

Section: Discussionmentioning

confidence: 99%

“…QseC is the membrane-bound sensor protein of the TCS with histidine kinase activity, and QseB is the cytoplasmic response regulator that regulates the expression of downstream target genes. QseC/QseB homologs are present in many important human and plant pathogens and are important for the virulence of pathogens (35)(36)(37). In enterohemorrhagic E. coli, QseC/QseB regulates multiple virulence factors and is known to respond to human epinephrine/norepinephrine and bacterial AI-3 (autoinducer 3), a group of mysterious signals whose identity is yet to be discovered (35)(36)(37)(38)(39)(40).…”

Section: Importancementioning

confidence: 99%

“…QseC/QseB homologs are present in many important human and plant pathogens and are important for the virulence of pathogens (35)(36)(37). In enterohemorrhagic E. coli, QseC/QseB regulates multiple virulence factors and is known to respond to human epinephrine/norepinephrine and bacterial AI-3 (autoinducer 3), a group of mysterious signals whose identity is yet to be discovered (35)(36)(37)(38)(39)(40). QseC is considered a target for new antibiotic development, and a potent QseC inhibitor, LED209, was identified (35,41,42).…”

Section: Importancementioning

confidence: 99%

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Indole-Induced Reversion of Intrinsic Multiantibiotic Resistance in Lysobacter enzymogenes

Han

Wang

et al. 2017

Appl Environ Microbiol

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species are a group of environmental bacteria that are emerging as a new source of antibiotics. One characteristic of is intrinsic resistance to multiple antibiotics, which had not been studied. To understand the resistance mechanism, we tested the effect of blocking two-component regulatory systems (TCSs) on the antibiotic resistance of, a prolific producer of antibiotics. Upon treatment with LED209, an inhibitor of the widespread TCS QseC/QseB, produced a large amount of an unknown metabolite that was barely detectable in the untreated culture. Subsequent structural elucidation by nuclear magnetic resonance (NMR) unexpectedly revealed that the metabolite was indole. Indole production was also markedly induced by adrenaline, a known modulator of QseC/QseB. Next, we identified two TCS genes, () and , in and found that mutations of and also led to a dramatic increase in indole production. We then chemically synthesized a fluorescent indole probe that could label the cells. While the (cytoplasmic response regulator) mutant was clearly labeled by the probe, the (membrane sensor) mutant was not labeled. It was reported previously that indole can enhance antibiotic resistance in bacteria. Therefore, we tested if the dramatic increase in the level of indole production in upon blocking of and would lead to enhanced antibiotic resistance. Surprisingly, we found that indole caused the intrinsically multiantibiotic-resistant bacterium to become susceptible. Point mutations at conserved amino acids in -QseC also led to antibiotic susceptibility. Because indole is known as an interspecies signal, these findings may have implications. The environmental bacterium is a new source of antibiotic compounds and exhibits intrinsic antibiotic resistance. Here, we found that the inactivation of a two-component regulatory system (TCS) by an inhibitor or by gene deletion led to a remarkable increase in the level of production of a metabolite in, and this metabolite was identified to be indole. We chemically synthesized a fluorescent indole probe and found that it could label the wild type and a mutant of the TCS cytoplasmic response regulator but not a mutant of the TCS membrane sensor. Indole treatment caused the intrinsically multidrug-resistant bacterium to be susceptible to antibiotics. Mutations of the TCS sensor also led to antibiotic susceptibility. Because indole is known as an interspecies signal between gut microbiota and mammalian hosts, the observation that indole could render intrinsically resistant susceptible to common antibiotics may have implications.

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Section: Discussionmentioning

confidence: 99%

Section: Importancementioning

confidence: 99%

Section: Importancementioning

confidence: 99%

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Indole-Induced Reversion of Intrinsic Multiantibiotic Resistance in Lysobacter enzymogenes

Han

Wang

et al. 2017

Appl Environ Microbiol

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“…Several studies have suggested the modulatory role of Hha in enterobacteria through its interaction with DNA regulatory sequences ( Fahlen et al, 2001 ; Sharma and Zuerner, 2004 ; Sharma et al, 2005 ; Sharma and Bearson, 2013 ; Sharma and Casey, 2014 ). It is worth to remark that only in one of these reports ( Olekhnovich and Kadner, 2007 ) the Hha protein has been purified in an Δ hns genetic background.…”

Section: Discussionmentioning

confidence: 99%

Hha has a defined regulatory role that is not dependent upon H-NS or StpA

et al. 2015

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The Hha family of proteins is involved in the regulation of gene expression in enterobacteria by forming complexes with H-NS-like proteins. Whereas several amino acid residues of both proteins participate in the interaction, some of them play a key role. Residue D48 of Hha protein is essential for the interaction with H-NS, thus the D48N substitution in Hha protein abrogates H-NS/Hha interaction. Despite being a paralog of H-NS protein, StpA interacts with HhaD48N with higher affinity than with the wild type Hha protein. To analyze whether Hha is capable of acting independently of H-NS and StpA, we conducted transcriptomic analysis on the hha and stpA deletion strains and the hhaD48N substitution strain of Salmonella Typhimurium using a custom microarray. The results obtained allowed the identification of 120 genes regulated by Hha in an H-NS/StpA-independent manner, 38% of which are horizontally acquired genes. A significant number of the identified genes are involved in functions related to cell motility, iron uptake, and pathogenicity. Thus, motility assays, siderophore detection and intra-macrophage replication assays were performed to confirm the transcriptomic data. Our findings point out the importance of Hha protein as an independent regulator in S. Typhimurium, highlighting a regulatory role on virulence.

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“…Finally, two recent studies suggest that the transcription of the qseBC operon is also regulated by nucleoid‐associated proteins. Sharma & Casey () demonstrated that deletion of hha resulted in a decrease in motility of EHEC and compared the contribution and hierarchy of Hha and QseBC in controlling EHEC motility. Using single and double gene deletion mutants, they showed that transcription of qseC was significantly reduced in a hha ‐deficient background relative to wild‐type or a complemented strain and that hha was hierarchically superior to qseBC in regulating motility.…”

Section: Activation Of Qseb and Transcriptional Regulation Of Qsebcmentioning

confidence: 99%

QseBC, a two‐component bacterial adrenergic receptor and global regulator of virulence in Enterobacteriaceae and Pasteurellaceae

Weigel

Demuth

2015

Molecular Oral Microbiology

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SummaryThe QseBC two‐component system (TCS) is associated with quorum sensing and functions as a global regulator of virulence. Based on sequence similarity within the sensor domain and conservation of an acidic motif essential for signal recognition, QseBC is primarily distributed in the Enterobacteriaceae and Pasteurellaceae. In Escherichia coli, QseC responds to autoinducer‐3 and/or epinephrine/norepinephrine. Binding of epinephrine/norepinephrine is inhibited by adrenergic antagonists; hence QseC functions as a bacterial adrenergic receptor. Aggregatibacter actinomycetemcomitans QseC is activated by a combination of epinephrine/norepinephrine and iron, whereas only iron activates the Haemophilus influenzae sensor. QseC phosphorylates QseB but there is growing evidence that QseB is activated by non‐cognate sensors and regulated by dephosphorylation via QseC. Interestingly, the QseBC signaling cascades and regulons differ significantly. In enterohemorrhagic E. coli, QseC induces expression of a second adrenergic TCS and phosphorylates two non‐cognate response regulators, each of which induces specific sets of virulence genes. This signaling pathway integrates with other regulatory mechanisms mediated by transcriptional regulators QseA and QseD and a fucose‐sensing TCS and likely controls the level and timing of virulence gene expression. In contrast, A. actinomycetemcomitans QseC signals through QseB to regulate genes involved in anaerobic metabolism and energy production, which may prime cellular metabolism for growth in an anaerobic host niche. QseC represents a novel target for therapeutic intervention and small molecule inhibitors already show promise as broad‐spectrum antimicrobials. Further characterization of QseBC signaling may identify additional differences in QseBC function and inform further development of new therapeutics to control microbial infections.

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Determining the Relative Contribution and Hierarchy of hha and qseBC in the Regulation of Flagellar Motility of Escherichia coli O157:H7

Cited by 10 publications

References 58 publications

Indole-Induced Reversion of Intrinsic Multiantibiotic Resistance in Lysobacter enzymogenes

Indole-Induced Reversion of Intrinsic Multiantibiotic Resistance in Lysobacter enzymogenes

Hha has a defined regulatory role that is not dependent upon H-NS or StpA

QseBC, a two‐component bacterial adrenergic receptor and global regulator of virulence in Enterobacteriaceae and Pasteurellaceae

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