Cholera Toxin Production during Anaerobic Trimethylamine N-Oxide Respiration Is Mediated by Stringent Response in Vibrio cholerae

Oh, Young Taek; Park, Yong‐Jin; Yoon, Mi Young; Bari, Wasimul; Go, Junhyeok; Min, Kyung Bae; Raskin, David M.; Lee, Kang-Mu; Yoon, Sang Sun

doi:10.1074/jbc.m113.540088

Cited by 23 publications

(34 citation statements)

References 63 publications

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“…Indeed, studies have shown that the virulence of enteric pathogens is associated with their ability to alter metabolic substrates in accordance with the intestinal environment of the host, which is constantly changing (45,46). Consistent with this notion, cholera toxin production was greatly induced when V. cholerae was grown by anaerobic TMAO respiration, a potential mode of growth that may occur inside the host intestine (31).…”

Section: Discussionsupporting

confidence: 65%

“…Additionally, bacterial SR has been shown to be important to the persistent survival (62,63) and virulence (64,65) of bacterial pathogens. Likewise, a V. cholerae (p)ppGpp 0 mutant showed defective intestinal colonization and cholera toxin production, compared with its parental strain (31). The production of virulence factors has been shown to increase when bacterial cells encounter extracellular stress, often resulting in retarded growth (7, 66 -68).…”

Section: Discussionmentioning

confidence: 99%

“…1A). Because the initial growth defect caused by accumulation of (p)ppGpp is a hallmark of the SR, the ⌬relA⌬spoT double mutant, which is the (p)ppGpp overproducing strain, has been characterized as having slow growth (31). When grown in LBG, …”

Section: Construction Of a Random Transposon Insertion Mutantmentioning

confidence: 99%

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(p)ppGpp, a Small Nucleotide Regulator, Directs the Metabolic Fate of Glucose in Vibrio cholerae

Lee

Bari

et al. 2015

Journal of Biological Chemistry

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Background: Bacteria respond to nutrient starvation by (p)ppGpp that activates the stringent response. Results: V. cholerae mutants defective in (p)ppGpp production lost their viability during glucose-supplemented growth because of overproduction of organic acids. Conclusion: (p)ppGpp regulates energy metabolism, contributing to the successful proliferation of V. cholerae under glucoserich environments. Significance: We report a previously unexplored role of (p)ppGpp in V. cholerae glucose metabolism.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

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(p)ppGpp, a Small Nucleotide Regulator, Directs the Metabolic Fate of Glucose in Vibrio cholerae

Lee

Bari

et al. 2015

Journal of Biological Chemistry

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“…The reduced needs of these cells appear to contribute significantly to environmental survival when conditions are unfavorable. Both QS and passage through a mammalian host return these cells to their active state, indicating that recovery from this state plays a significant role in transmission and the start of outbreaks (147–150). …”

Section: Mechanisms Of Environmental Survival and Factors Influencingmentioning

confidence: 99%

Staying Alive: Vibrio cholerae ’s Cycle of Environmental Survival, Transmission, and Dissemination

et al. 2016

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Infectious diseases kill nearly 9 million people annually. Bacterial pathogens are responsible for a large proportion of these diseases and the bacterial agents of pneumonia, diarrhea, and tuberculosis are leading causes of death and disability worldwide (1). Increasingly, the crucial role of non-host environments in the life cycle of bacterial pathogens is being recognized. Heightened scrutiny has been given to the biological processes impacting pathogen dissemination and survival in the natural environment, as these processes are essential for the transmission of pathogenic bacteria to new hosts. This chapter focuses on the model environmental pathogen, Vibrio cholerae, to describe recent advances in our understanding of how pathogens survive between hosts and highlight the processes necessary to support the cycle of environmental survival, transmission, and dissemination. We describe the physiological and molecular responses of V. cholerae to changing environmental conditions, focusing on its survival in aquatic reservoirs between hosts and its entry and exit from human hosts.

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“…Further, this increased production was suppressed when V. cholerae was unable to produce (p)ppGpp (Oh et al, 2014). In addition, CT production during the AKI condition (a biphasic growth to promote CT production; Iwanaga et al, 1986) is dependent on the cell's capability to produce (p)ppGpp (Oh et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Selective and Efficient Elimination of Vibrio cholerae with a Chemical Modulator that Targets Glucose Metabolism

Kim

et al. 2016

Front. Cell. Infect. Microbiol.

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Vibrio cholerae, a Gram-negative bacterium, is the causative agent of pandemic cholera. Previous studies have shown that the survival of the seventh pandemic El Tor biotype V. cholerae strain N16961 requires production of acetoin in a glucose-rich environment. The production of acetoin, a neutral fermentation end-product, allows V. cholerae to metabolize glucose without a pH drop, which is mediated by the production of organic acid. This finding suggests that inhibition of acetoin fermentation can result in V. cholerae elimination by causing a pH imbalance under glucose-rich conditions. Here, we developed a simple high-throughput screening method and identified an inducer of medium acidification (iMAC). Of 8364 compounds screened, we identified one chemical, 5-(4-chloro-2-nitrobenzoyl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, that successfully killed glucose-metabolizing N16961 by inducing acidic stress. When N16961 was grown with abundant glucose in the presence of iMAC, acetoin production was completely suppressed and concomitant accumulation of lactate and acetate was observed. Using a beta-galactosidase activity assay with a single-copy palsD::lacZ reporter fusion, we show that that iMAC likely inhibits acetoin production at the transcriptional level. Thin-layer chromatography revealed that iMAC causes a significantly reduced accumulation of intracellular (p)ppGpp, a bacterial stringent response alarmone known to positively regulate acetoin production. In vivo bacterial colonization and fluid accumulation were also markedly decreased after iMAC treatment. Finally, we demonstrate iMAC-induced bacterial killing for 22 different V. cholerae strains belonging to diverse serotypes. Together, our results suggest that iMAC, acting as a metabolic modulator, has strong potential as a novel antibacterial agent for treatment against cholera.

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Cholera Toxin Production during Anaerobic Trimethylamine N-Oxide Respiration Is Mediated by Stringent Response in Vibrio cholerae

Cited by 23 publications

References 63 publications

(p)ppGpp, a Small Nucleotide Regulator, Directs the Metabolic Fate of Glucose in Vibrio cholerae

(p)ppGpp, a Small Nucleotide Regulator, Directs the Metabolic Fate of Glucose in Vibrio cholerae

Staying Alive: Vibrio cholerae ’s Cycle of Environmental Survival, Transmission, and Dissemination

Selective and Efficient Elimination of Vibrio cholerae with a Chemical Modulator that Targets Glucose Metabolism

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