Identification of Three Antimicrobials Activating Serotonin Receptor 4 in Colon Cells.,ACS Synthetic Biology

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Identification of Three Antimicrobials Activating Serotonin Receptor 4 in Colon Cells.
ACS Synthetic Biology ( IF 3.7 ) Pub Date : 2019-11-12 , DOI: 10.1021/acssynbio.9b00310
Emily A Yasi ₁ , Aurelia A Allen ₁ , Widianti Sugianto ₁ , Pamela Peralta-Yahya _{1,

2}

Affiliation

The serotonin receptor 4b (5-HTR4b) is expressed throughout the gastrointestinal tract, and its agonists are used in the treatment of irritable bowel syndrome with constipation (IBS-C). Today, there are no rapid assays for the identification of 5-HTR4b agonists. Here, we developed a luciferase-based 5-HTR4b assay capable of assessing one compound per second with a 38-fold dynamic range and nM limit of detection for serotonin. We used the assay to screen more than 1000 natural products and anti-infection agents and identified five new 5-HTR4b ligands: hordenine, halofuginone, proflavine, ethacridine, and revaprazan. We demonstrate that hordenine (antibiofilm), halofuginone (antiparasitic), and revaprazan (gastric acid reducer) activate 5-HTR4b in human colon epithelial cells, leading to increased cell motility or wound healing. The 5-HTR4b assay can be used to screen larger pharmaceutical libraries to identify novel treatments for IBS-C. This work shows that antimicrobials interact not only with the gut microbiota, but also with the human host.

中文翻译：

在结肠细胞中激活三种抗菌素激活血清素受体4的鉴定。

血清素受体4b（5-HTR4b）在整个胃肠道中都有表达，其激动剂用于治疗便秘型肠易激综合症（IBS-C）。如今，尚无用于鉴定5-HTR4b激动剂的快速测定法。在这里，我们开发了一种基于萤光素酶的5-HTR4b检测方法，能够以每秒38倍的动态范围和nM血清素检测极限来评估一种化合物。我们使用该分析方法筛选了1000多种天然产物和抗感染剂，并鉴定了5种新的5-HTR4b配体：鱼藤碱，氟丁酮，前黄酮，乙ha啶和瑞伐拉赞。我们证明了大麦碱（抗生物膜），氟丁酮（抗寄生虫药）和瑞伐拉赞（胃酸还原剂）激活人结肠上皮细胞中的5-HTR4b，从而导致细胞运动性或伤口愈合增加。5-HTR4b分析可用于筛选更大的药物文库，以鉴定IBS-C的新疗法。这项工作表明，抗菌剂不仅与肠道菌群相互作用，而且还与人类宿主相互作用。

更新日期：2019-11-13

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