Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Gerratana, Barbara

doi:10.1002/med.20212

Cited by 118 publications

(146 citation statements)

References 185 publications

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“…The structure of tilivalline is also highly similar to PBD antitumor antibiotics of Streptomyces, Streptosporangium, and Micrococcus species. Substances of this class share the PBD structural backbone, which is exclusively synthesized via NRPS (43). Most described PBDs are secondary metabolites of Actinomycetes, with A and B) (n = 3).…”

Section: Discussionmentioning

confidence: 99%

Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis

Schneditz

Rentner

Roier

et al. 2014

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

103

181

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Antibiotic therapy disrupts the human intestinal microbiota. In some patients rapid overgrowth of the enteric bacterium Klebsiella oxytoca results in antibiotic-associated hemorrhagic colitis (AAHC). We isolated and identified a toxin produced by K. oxytoca as the pyrrolobenzodiazepine tilivalline and demonstrated its causative action in the pathogenesis of colitis in an animal model. Tilivalline induced apoptosis in cultured human cells in vitro and disrupted epithelial barrier function, consistent with the mucosal damage associated with colitis observed in human AAHC and the corresponding animal model. Our findings reveal the presence of pyrrolobenzodiazepines in the intestinal microbiota and provide a mechanism for colitis caused by a resident pathobiont. The data link pyrrolobenzodiazepines to human disease and identify tilivalline as a target for diagnosis and neutralizing strategies in prevention and treatment of colitis.bacteria | enteric microbiota | cytotoxin

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Section: Discussionmentioning

confidence: 99%

Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis

Schneditz

Rentner

Roier

et al. 2014

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

103

181

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“…The NpsA/ThdA module is predicted to accept anthranilate substrates and NpsB l ‐proline 13. The aroX‐dhbX‐icmX‐adsX‐hmoX operon may provide the anthranilic substrate via enzymes related to the shikimate and chorismate pathways (Scheme 2) similar to the biosynthesis of the analogous PBDs anthramycin and tomaymycin 14. The 2‐keto‐3‐deoxy‐ d ‐arabino‐heptolosonate phosphate synthase AroX is independent of amino acid feedback regulation like its counterpart TomC in tomaymycin synthesis 14, 15.…”

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confidence: 99%

Biosynthesis of the Enterotoxic Pyrrolobenzodiazepine Natural Product Tilivalline

et al. 2017

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The nonribosomal enterotoxin tilivalline was the first naturally occurring pyrrolobenzodiazepine to be linked to disease in the human intestine. Since the producing organism Klebsiella oxytoca is part of the intestinal microbiota and the pyrrolobenzodiazepine causes the pathogenesis of colitis it is important to understand the biosynthesis and regulation of tilivalline activity. Here we report the biosynthesis of tilivalline and show that this nonribosomal peptide assembly pathway initially generates tilimycin, a simple pyrrolobenzodiazepine with cytotoxic properties. Tilivalline results from the non‐enzymatic spontaneous reaction of tilimycin with biogenetically generated indole. Through a chemical total synthesis of tilimycin we could corroborate the predictions made about the biosynthesis. Production of two cytotoxic pyrrolobenzodiazepines with distinct functionalities by human gut resident Klebsiella oxytoca has important implications for intestinal disease.

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“…Moreover, the microbiota in the intestine is able to produce metabolites with benzodiazepine-like structures and effects [40][41][42]. Specifically, benzodiazepine receptor ligands originating from the gut microbiota have been proposed to contribute to the encephalopathy associated with fulminant hepatic failure [40].…”

Section: Neuroactive Factors Released By the Gut Microbiotamentioning

confidence: 99%

Neuropeptides and the Microbiota-Gut-Brain Axis

Holzer

Farzi

2014

Advances in Experimental Medicine and Biology

366

290

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Neuropeptides are important mediators both within the nervous system and between neurons and other cell types. Neuropeptides such as substance P, calcitonin gene-related peptide and neuropeptide Y (NPY), vasoactive intestinal polypeptide, somatostatin and corticotropin-releasing factor are also likely to play a role in the bidirectional gut-brain communication. In this capacity they may influence the activity of the gastrointestinal microbiota and its interaction with the gutbrain axis. Current efforts in elucidating the implication of neuropeptides in the microbiota-gutbrain axis address 4 information carriers from the gut to the brain (vagal and spinal afferent neurons; immune mediators such as cytokines; gut hormones; gut microbiota-derived signalling molecules) and 4 information carriers from the central nervous system to the gut (sympathetic efferent neurons; parasympathetic efferent neurons; neuroendocrine factors involving the adrenal medulla; neuroendocrine factors involving the adrenal cortex). Apart from operating as neurotransmitters, many biologically active peptides also function as gut hormones. Given that neuropeptides and gut hormones target the same cell membrane receptors (typically G proteincoupled receptors), the two messenger roles often converge in the same or similar biological implications. This is exemplified by NPY and peptide YY (PYY), two members of the PP-fold peptide family. While PYY is almost exclusively expressed by enteroendocrine cells, NPY is found at all levels of the gut-brain and brain-gut axis. The function of PYY-releasing enteroendocrine cells is directly influenced by short chain fatty acids generated by the intestinal microbiota from indigestible fibre, while NPY may control the impact of the gut microbiota on inflammatory processes, pain, brain function and behaviour. Although the impact of neuropeptides on the interaction between the gut microbiota and brain awaits to be analysed, biologically active peptides are likely to emerge as neural and endocrine messengers in orchestrating the microbiotagut-brain axis in health and disease.

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Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Cited by 118 publications

References 185 publications

Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis

Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis

Biosynthesis of the Enterotoxic Pyrrolobenzodiazepine Natural Product Tilivalline

Neuropeptides and the Microbiota-Gut-Brain Axis

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