Redox-Mediated Inactivation of the Transcriptional Repressor RcrR is Responsible for Uropathogenic Escherichia coli’s Increased Resistance to Reactive Chlorine Species

Sultana, Sadia; Crompton, Mary E; Meurer, Kennadi; Jankiewicz, Olivia; Morales, Grace; Johnson, Colton; Horbach, Elise; Hoffmann, Kevin Pierre; Kr, Pooja; Shah, Ritika; Anderson, Greg M.; Mortimer, Nathan T.; Schmitz, Jonathan E.; Hadjifrangiskou, Maria; Foti, Alessandro; Dahl, Jan-Ulrik

doi:10.1128/mbio.01926-22

Cited by 8 publications

(8 citation statements)

References 111 publications

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“…Proteins constitute for >50% of the cellular macromolecules and are known to rapidly react with HOCl ( Hawkins and Davies, 2019 ). Numerous studies in different HOCl-treated bacterial species revealed the strong upregulation of the heat shock regulon, indicating an accumulation of misfolded proteins and supporting the idea that proteins are the major targets of HOCl ( Groitl et al, 2017 ; Gray et al, 2013b ; Sultana et al, 2022 ; Thakur et al, 2019 ; Tung et al, 2020 ; Hillion et al, 2017 ). Similarly, H 2 O 2 can cause substantial protein aggregation as the result of methionine and cysteine oxidation ( Imlay, 2008 ).…”

Section: A Year At the Forefront Of Bacterial Defense Systems Against...mentioning

confidence: 64%

“…Given the physiological significance of HOX exposure during infection, research in this field is rapidly evolving even though we are still far away from understanding the full picture of HOX defenses in bacteria. The bacterial response and defense strategies are expected to be critical for their ability to survive the immune cell attack, as reported by several recent studies ( Sultana et al, 2022 ; Fritsch et al, 2023 ; Foik et al, 2022 preprint). Moreover, independent studies confirmed that the presence of functional oxidative stress defense systems positively affects pathogen colonization in the host, emphasizing their importance for pathogenesis ( Peng et al, 2020 ; Dahl et al, 2017 ; Hryckowian and Welch, 2013 ; Bessaiah et al, 2019 ).…”

Section: Future Prospectsmentioning

confidence: 83%

“…Sultana et al reported that uropathogenic E. coli (UPEC) are substantially more resistant to HOCl and killing by neutrophils due to the presence of an additional HOCl-defense system that intestinal E. coli lack ( Sultana et al, 2022 ). The TetR-family transcriptional repressor RcrR is reversibly inactivated through HOCl-mediated cysteine oxidation leading to the de-repression of transcription of the rcrARB operon ( Fig.…”

Section: A Year At the Forefront Of Bacterial Defense Systems Against...mentioning

confidence: 99%

“…HOCl causes the formation of intermolecular disulfide bonds in RcrR, which results in conformational changes and contributes to RcrR's dissociation from the promoter. UPEC's increased HOCl resistance appears to be exclusively mediated by RcrB, a putative inner membrane protein of unknown function, as rcrB -deficient UPEC strains were similarly susceptible to HOCl as the HOCl-sensitive intestinal E. coli strains tested ( Sultana et al, 2022 ).…”

Section: A Year At the Forefront Of Bacterial Defense Systems Against...mentioning

confidence: 99%

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A Year at the Forefront of Bacterial Defense Systems Against Neutrophilic Oxidants

Sultana

Dahl

2023

Biology Open

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One challenge for invading pathogens represents the exposure to highly microbicidal hypohalous acids (HOX), such as hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). Generated at high concentrations by innate immune cells during phagocytosis, HOX kills the engulfed microbes through extensive macromolecular damage. However, microorganisms have evolved strategies to detoxify the oxidants and/or alleviate HOX-mediated damage, which improves their survival during HOX exposure. Many of these defense systems are bacteria-specific and therefore considered potential drug targets. Our minireview highlights recent (July 2021 to November 2022) advances in the field of microbial HOX defense systems and how these systems are regulated. We report recent progress on redox-sensing transcriptional regulators, two-component systems, and σ/anti-σ factors and review how oxidative modifications in these regulatory proteins affect the expression of their target genes. Moreover, we discuss novel studies that describe how HOCl affects the activity of redox-regulated enzymes and highlight mechanisms that bacteria employ to reduce HOSCN.

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Section: A Year At the Forefront Of Bacterial Defense Systems Against...mentioning

confidence: 64%

Section: Future Prospectsmentioning

confidence: 83%

Section: A Year At the Forefront Of Bacterial Defense Systems Against...mentioning

confidence: 99%

Section: A Year At the Forefront Of Bacterial Defense Systems Against...mentioning

confidence: 99%

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A Year at the Forefront of Bacterial Defense Systems Against Neutrophilic Oxidants

Sultana

Dahl

2023

Biology Open

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“…RclR also responds strongly to reactive chlorine compounds (Parker et al, 2013), and since the HOCl-responsive E. coli transcription factor NemR also appears to detect HOSCN (Kostyuk et al, 2022), we suspect that many cysteine-dependent HOCl-sensitive regulators in bacteria (da Cruz Nizer et al, 2020) may also respond to HOSCN, but this remains to be determined. A homolog of RclC has recently been characterized in uropathogenic E. coli (UPEC) and has been implicated in aiding with membrane stability when cells are exposed to HOCl (Sultana et al, 2022), but the mechanism by which it does so remains unknown.…”

Section: Reiter Et Al Observed Bactericidal Effects Of Milk On Differ...mentioning

confidence: 99%

Hypothiocyanite and host–microbe interactions

Meredith

Gray

2023

Molecular Microbiology

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The pseudohypohalous acid hypothiocyanite/hypothiocyanous acid (OSCN − /HOSCN) has been known to play an antimicrobial role in mammalian immunity for decades. It is a potent oxidant that kills bacteria but is non-toxic to human cells. Produced from thiocyanate (SCN − ) and hydrogen peroxide (H 2 O 2 ) in a variety of body sites by peroxidase enzymes, HOSCN has been explored as an agent of food preservation, pathogen killing, and even improved toothpaste. However, despite the well-recognized antibacterial role HOSCN plays in host-pathogen interactions, little is known about how bacteria sense and respond to this oxidant. In this work, we will summarize what is known and unknown about HOSCN in innate immunity and recent advances in understanding the responses that both pathogenic and non-pathogenic bacteria mount against this antimicrobial agent, highlighting studies done with three model organisms, Escherichia coli, Streptococcus spp., and Pseudomonas aeruginosa.

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Expression of RcrB confers resistance to hypochlorous acid in uropathogenicEscherichia coli

Crompton,

Gaessler,

Tawiah

et al. 2023

Preprint

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To eradicate bacterial pathogens, neutrophils are recruited to the sites of infection, where they engulf and kill microbes through the production of reactive oxygen and chlorine species (ROS/RCS). The most prominent RCS is antimicrobial oxidant hypochlorous acid (HOCl), which rapidly reacts with various amino acids side chains, including those containing sulfur and primary/tertiary amines, causing significant macromolecular damage. Pathogens like uropathogenicEscherichia coli(UPEC), the primary causative agent of urinary tract infections (UTIs), have developed sophisticated defense systems to protect themselves from HOCl. We recently identified the RcrR regulon as a novel HOCl defense strategy in UPEC. The regulon is controlled by the HOCl-sensing transcriptional repressor RcrR, which is oxidatively inactivated by HOCl resulting in the expression of its target genes, includingrcrB. rcrBencodes the putative membrane protein RcrB, deletion of which substantially increases UPEC's susceptibility to HOCl. However, many questions regarding RcrB's role remain open including whether (i) the protein's mode of action requires additional help, (ii)rcrARBexpression is induced by physiologically relevant oxidants other than HOCl, and (iii) expression of this defense system is limited to specific media and/or cultivation conditions. Here, we provide evidence that RcrB expression is sufficient toE. coli's protection from HOCl and induced by and protects from several RCS but not from ROS. RcrB plays a protective role for RCS-stressed planktonic cells under various growth and cultivation conditions but appears to be irrelevant for UPEC's biofilm formation.

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Redox-Mediated Inactivation of the Transcriptional Repressor RcrR is Responsible for Uropathogenic Escherichia coli’s Increased Resistance to Reactive Chlorine Species

Cited by 8 publications

References 111 publications

A Year at the Forefront of Bacterial Defense Systems Against Neutrophilic Oxidants

A Year at the Forefront of Bacterial Defense Systems Against Neutrophilic Oxidants

Hypothiocyanite and host–microbe interactions

Expression of RcrB confers resistance to hypochlorous acid in uropathogenicEscherichia coli

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