解密克雷伯氏菌产生的肠毒素

创作:Roxy 审核:小肠君 03月12日
产酸克雷伯氏菌肠毒素在人体肠道中产生,肠毒素Tilimycin(TM)和Tilivalline(TV)可扰乱细胞周期;
抗生素相关性出血性结肠炎中,两种肠毒素对肠道上皮凋亡现象均有作用;
TM与DNA相互作用激活细胞的损伤修复机制,导致DNA链断裂,增加克雷伯氏菌定植小鼠盲肠肠细胞的病变程度;
TV与微管蛋白结合,稳定微管结构,导致有丝分裂停滞;
TM与TV对人类细胞均具有细胞毒性,TM与吲哚反应可产生TV。
延伸阅读
PNAS [IF:9.58]

Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities

产酸克雷伯氏菌的肠毒素tilimycin和tilivalline具有明显的宿主DNA损伤和微管稳定作用

02-11, Article, 10.1073/pnas.1819154116more

Abstract:
Establishing causal links between bacterial metabolites and human intestinal disease is a significant challenge. This study reveals the molecular basis of antibiotic-associated hemorrhagic colitis (AAHC) caused by intestinal resident Klebsiella oxytoca. Colitogenic strains produce the nonribosomal peptides tilivalline and tilimycin. Here, we verify that these enterotoxins are present in the human intestine during active colitis and determine their concentrations in a murine disease model. Although both toxins share a pyrrolobenzodiazepine structure, they have distinct molecular targets. Tilimycin acts as a genotoxin. Its interaction with DNA activates damage repair mechanisms in cultured cells and causes DNA strand breakage and an increased lesion burden in cecal enterocytes of colonized mice. In contrast, tilivalline binds tubulin and stabilizes microtubules leading to mitotic arrest. To our knowledge, this activity is unique for microbiota-derived metabolites of the human intestine. The capacity of both toxins to induce apoptosis in intestinal epithelial cells—a hallmark feature of AAHC—by independent modes of action, strengthens our proposal that these metabolites act collectively in the pathogenicity of colitis.

First Authors:
Lisa Pöltl,Georg Schneditz

Correspondence Authors:
Ellen L Zechner

All Authors:
Katrin Unterhauser,Lisa Pöltl,Georg Schneditz,Sabine Kienesberger,Ronald A Glabonjat,Maksym Kitsera,Jakob Pletz,Fernando Josa-Prado,Elisabeth Dornisch,Christian Lembacher-Fadum,Sandro Roier,Gregor Gorkiewicz,Daniel Lucena,Isabel Barasoain,Wolfgang Kroutil,Marc Wiedner,Joanna I Loizou,Rolf Breinbauer,José Fernando Díaz,Stefan Schild,Christoph Högenauer,Ellen L Zechner