Evaluation of a Dual-Acting Antibacterial Agent, TNP-2092, on Gut Microbiota and Potential Application in the Treatment of Gastrointestinal and Liver Disorders.,ACS Infectious Diseases

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Evaluation of a Dual-Acting Antibacterial Agent, TNP-2092, on Gut Microbiota and Potential Application in the Treatment of Gastrointestinal and Liver Disorders.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-01-02 , DOI: 10.1021/acsinfecdis.9b00374
Ying Yuan ₁ , Xiaomei Wang ₁ , Xiangyi Xu ₁ , Yu Liu ₁ , Cancan Li ₂ , Meng Yang ₂ , Yiqing Yang ₃ , Zhenkun Ma ₁

Affiliation

TNP-2092 is a unique multitargeting drug conjugate with extremely low propensity for development of resistance. The in vitro activity of TNP-2092 against a panel of urease-producing bacteria was similar to that of rifaximin, a locally acting antibiotic approved for the treatment of hepatic encephalopathy, irritable bowel syndrome with diarrhea, and traveler's diarrhea. When given orally, TNP-2092 exhibited low absorption and the majority of compound was recovered in feces as parent. The impact of oral TNP-2092 on gut microbiota was investigated in rats. TNP-2092 was administered to rats by oral gavage for 7 days. Feces samples were collected and analyzed by 16S rRNA sequencing. Although the total amount of bacterial load appeared relatively unchanged before, during, and after treatment, significant changes in the relative abundance of certain gut bacteria at family and genus levels were observed. Some of the changes are known to be associated with improvement of symptoms associated with liver cirrhosis and hepatic encephalopathy. The observed effects of TNP-2092 on gut microbiota in rats were similar to those of rifaximin. In vivo, TNP-2092 demonstrated potent efficacy in a mouse Clostridium difficile infection model, superior to metronidazole and vancomycin, with no relapse observed after treatment. TNP-2092 is currently in clinical development for the treatment of symptoms associated with gastrointestinal and liver disorders.

中文翻译：

对肠道菌群的双效抗菌剂TNP-2092的评估及其在胃肠道和肝脏疾病治疗中的潜在应用。

TNP-2092是一种独特的多靶点药物偶联物，极易产生耐药性。TNP-2092对一组产生脲酶的细菌的体外活性与利福昔明相似，利福昔明是一种局部作用的抗生素，被批准用于治疗肝性脑病，肠易激综合征，腹泻和旅行者腹泻。口服时，TNP-2092表现出低吸收性，大多数化合物作为母体从粪便中回收。在大鼠中研究了口服TNP-2092对肠道菌群的影响。将TNP-2092经口管饲法给予大鼠7天。收集粪便样品并通过16S rRNA测序进行分析。尽管治疗前，治疗中和治疗后的细菌总含量相对不变，在家族和属水平上，观察到某些肠道细菌的相对丰度发生了显着变化。已知某些变化与改善与肝硬化和肝性脑病有关的症状有关。TNP-2092对大鼠肠道菌群的影响与利福昔明相似。在体内，TNP-2092在小鼠艰难梭菌感染模型中显示出强效疗效，优于甲硝唑和万古霉素，治疗后未见复发。TNP-2092目前正在临床开发中，用于治疗与胃肠道和肝脏疾病相关的症状。TNP-2092对大鼠肠道菌群的影响与利福昔明相似。在体内，TNP-2092在小鼠艰难梭菌感染模型中显示出强效疗效，优于甲硝唑和万古霉素，治疗后未见复发。TNP-2092目前正在临床开发中，用于治疗与胃肠道和肝脏疾病相关的症状。TNP-2092对大鼠肠道菌群的影响与利福昔明相似。在体内，TNP-2092在小鼠艰难梭菌感染模型中显示出强效疗效，优于甲硝唑和万古霉素，治疗后未见复发。TNP-2092目前正在临床开发中，用于治疗与胃肠道和肝脏疾病相关的症状。

更新日期：2019-12-18

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