Extracellular superoxide production by <i>Enterococcus faecalis</i> requires demethylmenaquinone and is attenuated by functional terminal quinol oxidases

Huycke, Mark M.; Moore, Dennis; Joyce, Wendy; Wise, Phillip D; Shepard, Laura; Kotake, Yashige; Gilmore, Michael S.

doi:10.1046/j.1365-2958.2001.02638.x

Cited by 174 publications

(125 citation statements)

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“…The main sources of ROS in E. faecalis are oxidative metabolism of glycerol and incomplete demethylmenaquinone reduction during the activity of the electron transport chain in the absence of heme (31,32). Since the FMC media lack both glycerol and heme, we speculated that the majority of H 2 O 2 produced under these conditions derives from the incomplete electron transport chain and subsequent superoxide dismutation by MnSOD.…”

Section: Linkage Of (P)ppgpp and Metal Homeostasismentioning

confidence: 99%

“…In E. faecalis, lack of (p)ppGpp severely affected the metabolic profile of the cell even in the absence of stress, resulting in a significant decrease in lactate production and a concomitant increase in the levels of formate, ethanol, and acetoin (18). As by-products of its metabolism, E. faecalis releases significant amounts of ROS, including superoxide and H 2 O 2 (31,32). We previously showed that the (p)ppGpp 0 strain produces ϳ5-fold more H 2 O 2 during exponential growth, likely due to the uncontrolled metabolic flux of this strain (18).…”

Section: Linkage Of (P)ppgpp and Metal Homeostasismentioning

confidence: 99%

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Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

2017

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In Enterococcus faecalis, the regulatory nucleotides pppGpp and ppGpp, collectively, (p)ppGpp, are required for growth in blood, survival within macrophages, and virulence. However, a clear understanding of how (p)ppGpp promotes virulence in E. faecalis and other bacterial pathogens is still lacking. In the host, the essential transition metals iron (Fe) and manganese (Mn) are not readily available to invading pathogens because of a host-driven process called nutritional immunity. Considering its central role in adaptation to nutritional stresses, we hypothesized that (p)ppGpp mediates E. faecalis virulence through regulation of metal homeostasis. Indeed, supplementation of serum with either Fe or Mn restored growth and survival of the Δrel ΔrelQ [(p)ppGpp 0 ] strain to wild-type levels. Using a chemically defined medium, we found that (p)ppGpp accumulates in response to either Fe depletion or Mn depletion and that the (p)ppGpp 0 strain has a strong growth requirement for Mn that is alleviated by Fe supplementation. Although inactivation of the nutrient-sensing regulator codY restored some phenotypes of the (p)ppGpp 0 strain, transcriptional analysis showed that the (p)ppGpp/CodY network does not promote transcription of known metal transporters. Interestingly, physiologic and enzymatic investigations suggest that the (p)ppGpp 0 strain requires higher levels of Mn in order to cope with high levels of endogenously produced reactive oxygen species (ROS). Because (p)ppGpp mediates antibiotic persistence and virulence in several bacteria, our findings have broad implications and provide new leads for the development of novel therapeutic and preventive strategies against E. faecalis and beyond. KEYWORDS (p)ppGpp, Enterococcus, manganese, metal homeostasis, nutritional immunity, oxidative stress E nterococcus faecalis is a common member of the human gut microbiota but also a leading cause of a number of hospital-acquired infections such as endocarditis and surgical wound and urinary tract infections (1). The association of this opportunistic pathogen with disease relies on its exceptional resilience, which allows it to prevail in the unfavorable hospital setting while providing a competitive advantage over other bacteria during both infection and treatment.Among the most prominent regulators involved in bacterial adaptation to stress are the nucleotide second messengers guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), collectively, (p)ppGpp, best known as the effectors of the stringent response (SR) (2). While initially discovered to accumulate in response to amino acid starvation, (p)ppGpp has also been shown to accumulate in response to restrictions in carbon, fatty acids, and iron, as well as in response to other nonnutritional stresses (3). During the SR, (p)ppGpp accumulation triggers transcriptional alterations that lead to general repression of rapid growth and simultaneous activation of stress survival, nutrient uptake, and biosynthesis pathways. In addition to its involvement in...

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Section: Linkage Of (P)ppgpp and Metal Homeostasismentioning

confidence: 99%

Section: Linkage Of (P)ppgpp and Metal Homeostasismentioning

confidence: 99%

Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

2017

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“…ROS are also produced during bacterial aerobic metabolism 5,6 . It is well established that M. tuberculosis has evolved multiple ways to detoxify RNS and ROS.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional characterization of the antioxidant response of Mycobacterium tuberculosis in vivo and during adaptation to hypoxia in vitro

Shi¹,

Sohaskey

North

et al. 2008

Tuberculosis

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SummaryTranscriptional profiling of antioxidant genes of M. tuberculosis was performed by real-time RT-PCR during mouse lung infection and during adaptation to gradual oxygen depletion in vitro. M. tuberculosis genes involved in major detoxification pathways of oxidative stress were not upregulated during chronic mouse lung infection, which is established in response to expression of host adaptive immunity. This result suggests that a major function of bacterial antioxidant enzymes is to protect from oxidants generated during the early, acute phase of infection. In vivo transcription profiles of bacterial antioxidant enzymes differed from those seen under adaptation to low oxygen in vitro, indicating differences between growth arrest in vivo and that induced by hypoxia in vitro.

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“…Indeed, oxidation of Mn(II) to Mn oxides by a common marine bacterium, Roseobacter AzwK-3b, was found to be a consequence of enzymatic extracellular production of O 2 − , which served as the terminal oxidant of Mn(II) (19). Although extracellular superoxide production has been documented in pathogenic bacteria (20) and phytoplankton (21), very little is known about the occurrence of this process in nonpathogenic heterotrophic bacteria. In contrast, production of extracellular superoxide is widespread throughout the fungal kingdom (22), where it is involved in host defense, posttranslational modification of proteins, hyphal branching, cell signaling, and cell differentiation (22,23).…”

mentioning

confidence: 99%

Mn(II) oxidation by an ascomycete fungus is linked to superoxide production during asexual reproduction

Hansel

Zeiner

Santelli

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

194

161

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Manganese (Mn) oxides are among the most reactive minerals within the environment, where they control the bioavailability of carbon, nutrients, and numerous metals. Although the ability of microorganisms to oxidize Mn(II) to Mn(III/IV) oxides is scattered throughout the bacterial and fungal domains of life, the mechanism and physiological basis for Mn(II) oxidation remains an enigma. Here, we use a combination of compound-specific chemical assays, microspectroscopy, and electron microscopy to show that a common Ascomycete filamentous fungus, Stilbella aciculosa , oxidizes Mn(II) to Mn oxides by producing extracellular superoxide during cell differentiation. The reactive Mn oxide phase birnessite and the reactive oxygen species superoxide and hydrogen peroxide are colocalized at the base of asexual reproductive structures. Mn oxide formation is not observed in the presence of superoxide scavengers (e.g., Cu) and inhibitors of NADPH oxidases (e.g., diphenylene iodonium chloride), enzymes responsible for superoxide production and cell differentiation in fungi. Considering the recent identification of Mn(II) oxidation by NADH oxidase-based superoxide production by a common marine bacterium ( Roseobacter sp.), these results introduce a surprising homology between some prokaryotic and eukaryotic organisms in the mechanisms responsible for Mn(II) oxidation, where oxidation appears to be a side reaction of extracellular superoxide production. Given the versatility of superoxide as a redox reactant and the widespread ability of fungi to produce superoxide, this microbial extracellular superoxide production may play a central role in the cycling and bioavailability of metals (e.g., Hg, Fe, Mn) and carbon in natural systems.

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Extracellular superoxide production by Enterococcus faecalis requires demethylmenaquinone and is attenuated by functional terminal quinol oxidases

Cited by 174 publications

References 58 publications

Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

Transcriptional characterization of the antioxidant response of Mycobacterium tuberculosis in vivo and during adaptation to hypoxia in vitro

Mn(II) oxidation by an ascomycete fungus is linked to superoxide production during asexual reproduction

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