Enterotoxigenic<i>Bacteroides fragilis</i>: a Rogue among Symbiotes

Sears, Cynthia L.

doi:10.1128/cmr.00053-08

Cited by 340 publications

(299 citation statements)

References 127 publications

(173 reference statements)

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“…In the absence of this flora, opportunistic microorganisms may colonize the intestine and lead to severe digestion alterations and gastrointestinal diseases. In addition, ETBF can be resistant to antibiotics such as penicillin, ampicillin, clindamycin, tetracycline, and metronidazole (2). Accordingly, there is a substantiated need for better understanding ETBF targets such as fragilysin and for the design of highly specific antimicrobials to tackle them, and detailed structural information greatly contributes to these aims.…”

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confidence: 99%

“…Analysis of clinical isolates reveals that the three isoforms are generally present simultaneously (2) and that fragilysin-1 is the most abundant (see table 9 in ref. 2). The three fragilysin isoforms are encoded by a chromosomal pathogenicity islet that is absent in nonenterotoxigenic strains.…”

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confidence: 99%

“…In addition to fragilysin, this island contains a second gene, mpII, which is countertranscribed and encodes a potential MP of similar size and moderate sequence identity (28-30%) to the three fragilysin isoforms. However, its potential role in ETBF pathogenesis remains to be established (2).…”

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confidence: 99%

“…Members of the genus Bacteroides comprise the majority of intestinal obligate anaerobes, of which Bacteroides fragilis is most frequently associated with disease. Enterotoxigenic B. fragilis (ETBF) strains colonize and affect humans and livestock, and they have been linked to intraabdominal abscesses, diarrhea, inflammatory bowel disease, anaerobic bacteremia, and colon cancer (1)(2)(3). In addition to the bacterial capsule, which induces abscess formation, the only identified virulence factor for ETBF is a 21-kDa zinc-dependent metallopeptidase (MP), termed fragilysin alias B. fragilis toxin (BFT) (4)(5)(6).…”

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Structure, function and latency regulation of a bacterial enterotoxin potentially derived from a mammalian adamalysin/ADAM xenolog

Goulas

Arolas

Gomis‐Rüth

2011

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

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Enterotoxigenic Bacteroides fragilis is the most frequent diseasecausing anaerobe in the intestinal tract of humans and livestock and its specific virulence factor is fragilysin, also known as B. fragilis toxin. This is a 21-kDa zinc-dependent metallopeptidase existing in three closely related isoforms that hydrolyze E-cadherin and contribute to secretory diarrhea, and possibly to inflammatory bowel disease and colorectal cancer. Here we studied the function and zymogenic structure of fragilysin-3 and found that its activity is repressed by a ∼170-residue prodomain, which is the largest hitherto structurally characterized for a metallopeptidase. This prodomain plays a role in both the latency and folding stability of the catalytic domain and it has no significant sequence similarity to any known protein. The prodomain adopts a novel fold and inhibits the protease domain via an aspartate-switch mechanism. The catalytic fragilysin-3 moiety is active against several protein substrates and its structure reveals a new family prototype within the metzincin clan of metallopeptidases. It shows high structural similarity despite negligible sequence identity to adamalysins/ADAMs, which have only been described in eukaryotes. Because no similar protein has been found outside enterotoxigenic B. fragilis, our findings support that fragilysins derived from a mammalian adamalysin/ADAM xenolog that was co-opted by B. fragilis through a rare case of horizontal gene transfer from a eukaryotic cell to a bacterial cell. Subsequently, this co-opted peptidase was provided with a unique chaperone and latency maintainer in the time course of evolution to render a robust and dedicated toxin to compromise the intestinal epithelium of mammalian hosts.bacterial endotoxin | human pathogen | zymogen activation

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Structure, function and latency regulation of a bacterial enterotoxin potentially derived from a mammalian adamalysin/ADAM xenolog

Goulas

Arolas

Gomis‐Rüth

2011

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

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“…ETBF have been epidemiologically associated with acute diarrheal diseases in humans and livestock, inflammatory bowel diseases (IBD), and colorectal cancer (reviewed in ref. 3). Exposure of intestinal epithelial cell lines to BFT results in cleavage of the cell adhesion and tumor suppressor protein E-cadherin, morphological alterations, activation of stress response signaling pathways, induction of cytokine secretion, and increased cellular proliferation mediated by elevated expression of the c-Myc oncogene (4)(5)(6)(7)(8)(9)(10)(11).…”

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confidence: 99%

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Goodwin¹,

Shields²,

Wu³

et al. 2011

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

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It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) upregulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N 1 ,N 4 -bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment with MDL 72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention.inflammatory bowel diseases | adenomatous polyposis coli I t is estimated that chronic inflammation associated with microbial infection directly contributes to the etiology of about 20% of epithelial cancers. The chronic inflammatory microenvironment is characterized by immune dysregulation and elevated levels of reactive oxygen species [ROS; including superoxide, hydrogen peroxide (H 2 O 2 ), and singlet oxygen]. These features result in activation of stress response pathways and oncogenes, down-regulation of tumor suppressor genes, cell and tissue damage, and contribute to tumor initiation, promotion, and progression. However, the precise molecular links between inflammation and carcinogenesis remain to be clarified (1, 2).In the colon, alterations in the physiological balance between the diverse and abundant microbiota (w10 12 organisms per gram feces) and the host are a common source of inflammation. Bacteroides spp comprise a significant proportion of colonic commensal bacteria and members of this group include symbionts and the leading human anaerobic pathogen, Bacteroides fragilis. Enterotoxigenic B. fragilis (ETBF) represent a molecular subtype characterized by a single unique virulence determinant, the production and secretion of a 20-kDa metalloprotease enterotoxin (B. fragilis toxin; BFT). ETBF have been epidemiologically associated with acute diarrheal diseases in humans and livestock, inflammatory bowel diseases (IBD), and colorectal cancer (reviewed in ref.3). Exposure of intestinal epithelial cell lines to BFT results in cleavage of the cell adhesion and tumor suppressor protein E-cadherin, ...

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Bacterial Infections

Hay,

Morris‐Jones

2016

Rook's Textbook of Dermatology, Ninth Edition

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This chapter starts by considering the resident bacterial population of the skin and how this has altered with our growing understanding of the skin microbiome. It then reviews the whole range of bacterial skin infections from primary Gram‐positive infections due to staphylococci and streptococci to the less common infections caused by Gram‐negative and anaerobic bacteria. The cutaneous manifestations of common and rare systemic bacterial infections such as staphylococcal septicaemia and melioidosis are described in practical detail. Using new work on antibiotics, the spread of drug resistance amongst skin bacterial pathogens is reviewed and its relevance clarified in the treatment algorithms. Rickettsial infections are also considered.

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EnterotoxigenicBacteroides fragilis: a Rogue among Symbiotes

Cited by 340 publications

References 127 publications

Structure, function and latency regulation of a bacterial enterotoxin potentially derived from a mammalian adamalysin/ADAM xenolog

Structure, function and latency regulation of a bacterial enterotoxin potentially derived from a mammalian adamalysin/ADAM xenolog

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Bacterial Infections

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