Biosynthesis of the Klebsiella oxytoca Pathogenicity Factor Tilivalline: Heterologous Expression, in Vitro Biosynthesis, and Inhibitor Development,ACS Chemical Biology

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Biosynthesis of the Klebsiella oxytoca Pathogenicity Factor Tilivalline: Heterologous Expression, in Vitro Biosynthesis, and Inhibitor Development
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-02-01 00:00:00 , DOI: 10.1021/acschembio.7b00990
Alexander von Tesmar ₁ , Michael Hoffmann ₁ , Antoine Abou Fayad ₁ , Stephan Hüttel ₂ , Viktoria Schmitt ₁ , Jennifer Herrmann ₁ , Rolf Müller ₁

Affiliation

Tilvalline is a pyrrolo[4,2]benzodiazepine derivative produced by the pathobiont Klebsiella oxytoca and is the causative toxin in antibiotic associated hemorrhagic colitis (AAHC). Heterologous expression of the tilivalline biosynthetic gene cluster along with in vitro reconstitution of the respective NRPS (NpsA, ThdA, NpsB) was employed to reveal a nonenzymatic indole incorporation via a spontaneous Friedel–Crafts-like alkylation reaction. Furthermore, the heterologous system was used to generate novel tilivalline derivatives by supplementation of respective anthranilate and indole precursors. Finally, it could be shown that salicylic and acetylsalicylic acid inhibit the biosynthesis of tilivalline in K. oxytoca liquid culture, presumably by blocking the peptidyl carrier protein ThdA, pointing toward a potential application in combination therapy to prevent or alleviate the symptoms of AAHC.

中文翻译：

在生物合成酸克雷伯菌致病因子Tilivalline：异源表达，体外生物合成和抑制剂发展

Tilvalline是由病原菌产酸克雷伯菌产生的吡咯并[4,2]苯并二氮杂derivative衍生物，是抗生素相关性出血性结肠炎（AAHC）的致病性毒素。罗非替林生物合成基因簇的异源表达以及相应的NRPS（NpsA，ThdA，NpsB）的体外重组用于通过自发的Friedel-Crafts样烷基化反应揭示非酶吲哚的掺入。此外，异源系统用于通过补充各自的邻氨基苯甲酸酯和吲哚前体来产生新的蒂罗伐林衍生物。最后，可以证明水杨酸和乙酰水杨酸抑制催产假单胞菌中丁草碱的生物合成。液体培养，大概是通过阻断肽基载体蛋白ThdA来进行的，它指出了在联合治疗中预防或减轻AHC症状的潜在应用。

更新日期：2018-02-01

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