Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis

被引：94

作者：

Schneditz, Georg ^{[1
]}

Rentner, Jana ^{[2
]}

Roier, Sandro ^{[1
]}

Pletz, Jakob ^{[2
]}

Herzog, Kathrin A. T. ^{[3
]}

Buecker, Roland ^{[5
]}

Troeger, Hanno ^{[5
]}

Schild, Stefan ^{[1
]}

Weber, Hansjoerg ^{[2
]}

Breinbauer, Rolf ^{[2
]}

Gorkiewicz, Gregor ^{[4
]}

Hoegenauer, Christoph ^{[3
]}

Zechner, Ellen L. ^{[1
]}

机构：

[1] Graz Univ, Inst Mol Biosci, A-8010 Graz, Austria

[2] Graz Univ Technol, Inst Organ Chem, A-8010 Graz, Austria

[3] Med Univ Graz, Dept Internal Med, Div Gastroenterol & Hepatol, A-8036 Graz, Austria

[4] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria

[5] Charite Campus Benjamin Franklin, Department Gastroenterol Infectiol & Rheumatol, D-10117 Berlin, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2014年 / 111卷 / 36期

基金：

奥地利科学基金会;

关键词：

bacteria; enteric microbiota; cytotoxin; PYRROLO(1,4)BENZODIAZEPINE ANTITUMOR ANTIBIOTICS; HIGH-PATHOGENICITY ISLAND; KLEBSIELLA-OXYTOCA; HEMORRHAGIC COLITIS; ESCHERICHIA-COLI; ASPERGILLUS-OCHRACEUS; SHIKIMATE PATHWAY; GUT MICROBIOTA; SIBIROMYCIN; BIOSYNTHESIS;

D O I：

10.1073/pnas.1403274111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：13181 / 13186

页数：6

共 51 条

[21] PYRROLO[1,4]BENZODIAZEPINE ANTIBIOTICS - BIOSYNTHESIS OF THE ANTI-TUMOR ANTIBIOTIC SIBIROMYCIN BY STREPTOSPORANGIUM-SIBIRICUM [J].