Niclosamide

引言 药物会影响人体肠道微生物组的组成和功能【1-2】。研究表明，数百种药物（如抗生素）会直接抑制肠道共生菌的生长【3-4】。反之，肠道微生物对药物的代谢或吸收也会影响药物的生物利用度和药效【1,5】。近年来，随着肠道微生物培养技术的进步，越来越多的研究开始大规模探索不同药物与肠道微生物之间的相互作用。然而，对于“单一物种与药物的相互作用在群落状态下是否会受到影响”这一问题，人们仍知之甚少。 近日，欧洲分子生物学实验室（EMBL）Athanasios Typas、Peer Bork、Michael Zimmermann和Kiran R. Patil团队共同在Cell杂志上发表了题为Emergence of community behaviors in the gut microbiota upon drug treatment的文章。该研究比较了30种药物对含有32种菌的人工合成群落的影响以及对每个群落成员的单独影响，发现当药物作用于群落时，微生物成员的相互作用会导致群落行为的涌现，从而改变微生物成员对药物的敏感性。 首先，作者构建了一个由32种代表性肠道微生物（来自6个门、26个属）组成的人工合成群落，并根据其之前的研究【3】筛选出了30种具有代表性的药物（能抑制不同微生物的生长且涵盖多个不治疗领域），以测试肠道微生物和药物之间的相互作用。 作者将不同浓度的药物加入到人工合成群落或单一物种培养物中，并比较其对不同物种生长的影响。比较结果可分为3种：（1）不存在差异，在群落和单一培养条件下，微生物生长受到类似影响或均不受影响；（2）交叉敏感化（cross-sensitization），微生物在单独生长时不受到药物影响（耐药），但在群落状态下受到抑制、丰度降低；（3）交叉保护（cross-protection），微生物在单独生长时受到药物的抑制作用（对药物敏感），但在群落状态下生长正常。 结果显示，在群落环境中，大部分（74%）药物-微生物成员之间的相互作用不变，但每种药物都会引发群落行为，共有26%的药物-微生物成员之间的相互发生了变化。当仅考虑对药物敏感的物种时，发生交叉保护作用的测试占全部测试的47%；当仅考虑耐药的物种时，发生交叉敏感化的测试占全部测试的8%。上述结果提示在进行药物治疗后，人体肠道微生物组会出现许多交叉保护或交叉敏感化事件，且由于不同个体的肠道微生物组不同，上述群落事件可能会因人而异。 比较3种药物浓度的结果，作者发现，随着药物浓度的增加，群落中受到保护的物种减少，敏感物种增加。这表明在低药物浓度下，群落可以抵抗干扰，而在高浓度下，群落会发生崩溃，不仅无法保护敏感物种，且还有可能由于微生物之间的相互作用导致原本具有抗性的物种生长受到抑制。 微生物对药物的代谢转化或吸收积累作用可能是引发交叉保护或交叉敏感化的机制。由于大部分群落行为属于交叉保护作用，因此作者进一步探究了交叉保护作用背后的机制。为此，作者使用LC-MS测量了药物浓度随时间的变化，并通过比较整个群落（包含上清液和细菌）样本与上清液样本来区分生物转化作用和生物积累作用。 结果显示，药物生物转化和生物积累在一定程度上可以解释群落产生的交叉保护现象。例如，质子泵抑制剂兰索拉唑的衰变会因微生物群落而加快；抗寄生虫药物氯硝柳胺会被微生物群落快速代谢；抗疟疾药物甲氟喹既存在生物积累作用，也存在生物转化作用。并且作者发现，在该研究的大多数情况下，药物生物转化会产生无害或毒性较小的物质。 接着作者进一步聚焦了3种药物芳香硝基化合物——抗寄生虫药物氯硝柳胺和硝呋莫司以及治疗帕金森病的药物恩他卡朋。结果显示，不同物种对同一药物的耐药机制不同，从而会对群落产生不同影响。如Roseburia intestinalis、Coprococcus comes和具核梭杆菌能够还原氯硝柳胺，使其失去活性，大幅降低群落环境中该药物的浓度，从而保护其他敏感物种。而大肠杆菌无法降解该药物，但可在其胞内积累，因此难以为其他敏感物种提供保护作用。利用上述结果，作者发现其可以设计出更能抵抗药物治疗的群落，即通过向对氯硝柳胺敏感的小群落中加入C. comes可以有效恢复群落的生长。 最后作者鉴定确定了与氯硝柳胺交叉保护作用相关的硝基还原酶（可还原芳香硝基化合物），其重点研究了两个物种：（1）R. intestinalis，对氯硝柳胺具有中等抗性且能够为其他敏感物种提供保护作用，编码2种假定的硝基还原酶；（2）Phocaeicola vulgatus，对氯硝柳胺敏感，但编码了7种假定的硝基还原酶。结果显示，过表达2种R. intestinalis硝基还原酶中的任何一种，都会使P. vulgatus对氯硝柳胺更加耐受。然而，有趣的是过表达P. vulgatus中的2种硝基还原酶也会使其变得更耐受。进一步检测蛋白质浓度发现，尽管这2种酶能够还原氯硝柳胺，但是其在P. vulgatus中的表达浓度很低，而2种R. intestinalis硝基还原酶的表达量都很高。上述结果表明，尽管很多物种都可能具有药物生物转化能力，但是在药物治疗后并不一定会大量表达相关的酶。 模式图（Credit: Cell） 综上，该研究表明大多数药物-肠道细菌的相互作用在群落中保持不变，但是交叉保护作用和交叉敏感化几乎会发生在每种药物上。该研究有助于建立更精确的药物-肠道微生物预测模型，预测肠道微生物群落对药物的响应，并进一步强调了在药物设计过程中需要考虑肠道微生物因素。 参考文献 1. Zimmermann, M., Patil, K.R., Typas, A., and Maier, L. (2021). Towards a mechanistic understanding of reciprocal drug–microbiome interactions. Mol. Syst. Biol. 17, e10116. https://doi.org/10.15252/MSB.202010116. 2. Maier, L., and Typas, A. (2017). Systematically investigating the impact of medication on the gut microbiome. Curr. Opin. Microbiol. 39, 128–135. https://doi.org/10.1016/J.MIB.2017.11.001. 3. Maier, L., Pruteanu, M., Kuhn, M., Zeller, G., Telzerow, A., Anderson, E.E., Brochado, A.R., Fernandez, K.C., Dose, H., Mori, H., et al. (2018). Exten- sive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628. https://doi.org/10.1038/nature25979. 4. Maier, L., Goemans, C.V., Wirbel, J., Kuhn, M., Eberl, C., Pruteanu, M., Mu ̈ ller, P., Garcia-Santamarina, S., Cacace, E., Zhang, B., et al. (2021). Unravelling the collateral damage of antibiotics on gut bacteria. Nature 599, 120–124. https://doi.org/10.1038/s41586-021-03986-2. 5. Klu ̈ nemann, M., Andrejev, S., Blasche, S., Mateus, A., Phapale, P., Deven- dran, S., Vappiani, J., Simon, B., Scott, T.A., Kafkia, E., et al. (2021). Bio- accumulation of therapeutic drugs by human gut bacteria. Nature 7877, 533–538. https://doi.org/10.1038/s41586-021-03891-8. https://doi.org/10.1016/j.cell.2024.08.037 责编|探索君 排版|探索君 来源|BioArt End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述

SAN DIEGO, Sept. 17, 2024 /PRNewswire/ -- Hyundai Bioscience USA announced that it has signed an MOU with the University of California San Diego (UCSD) to conduct an investigator-initiated trial to evaluate the efficacy of Xafty®, a niclosamide-based antiviral developed by its Korean headquarters, in treating "Long-COVID". The trial will be led by UCSD Professor Ajay Bharti, an infectious disease specialist and clinical trialist. Dr. Bharti's particular expertise in the neurocognitive effects of viral illnesses make him perfectly suited to run the investigator initiated trial. "This is an outstanding opportunity for UC San Diego and Hyundai Bioscience to partner together to tackle Long-COVID," Professor. Davey Smith, Director of the UCSD Altman Clinical and Translational Research Institute (ACTRI) of UCSD and an authority on viral illnesses, especially COVID, said about the collaboration. "There is no therapy currently available for the condition, which affects millions of people around the world." Xafty, an oral antiviral agent, is a new drug that improved the bioavailability of niclosamide, which is known to have antiviral efficacy against more than 30 viruses. It is currently in a phase 3 clinical trial in Korea targeting high-risk groups for COVID-19 and is expected to apply for phase 3 to the U.S. FDA soon. In a previous phase 2 clinical trial, Xafty successfully met the FDA's primary endpoints, demonstrating a faster symptom improvement rate than other existing treatments, especially in high-risk groups. "Being able to reduce symptoms during acute COVID-19 is an impressive accomplishment," Dr. Smith, who has helped run numerous antiviral trials in COVID-19, HIV, and Mpox, said. "Many large recent trials testing antivirals have not had such success. This may point to Xafty's effectiveness in Long-COVID as well." Long-COVID is a complex disease that is suggested to be caused by residual virus, excessive inflammation, and consequent nerve damage. Patients suffer from various symptoms such as chronic fatigue, inflammation, and cognitive decline, but existing treatments rely on a single mechanism and fail to resolve these complex symptoms. This is one of the reasons why a clear treatment for Long-COVID has not yet been developed. Xafty is expected to resolve the complex symptoms of Long-COVID through inflammation inhibition and neuro-protection mechanisms, rather than simply suppressing the virus. It is because niclosamide, Xafty's main pharmaceutical ingredient, is anticipated to provide practical therapeutic effects to patients through multiple mechanisms such as virus removal, suppression of immune hypersensitivity, and recovery of nerve damage. In a recent Parkinson's disease preclinical study conducted by Hyundai Bioscience, Xafty demonstrated to promote dopamine production and nerve cell recovery. When Xafty was administered to a Parkinson's animal model with suppressed dopamine production, a higher dopamine level was confirmed than in the group administered with the existing Parkinson's disease treatment, dopamine precursor (Madopar®), suggesting that it can make a significant contribution to improving symptoms such as brain fog and cognitive impairment due to nerve damage in people with Long-COVID. Dr. Ajay Bharti, the PI of this study, said, "We already knew about the broad-spectrum antiviral efficacy of niclosamide, but after seeing data showing that Xafty, having improved the long-standing problem of bioavailability, showed excellent symptom improvement in a COVID-19 clinical trial, especially in the high-risk group, we came up with the idea of using the drug to treat Long COVID." He added, "In particular, the fact that Xafty recovered neurons in a preclinical study of Parkinson's disease and promoted dopamine production, resulting in higher dopamine levels than the control group that took Madopar®, was an important trigger for this clinical study." Dr. Smith added, "The goal of this study is to confirm that niclosamide can solve the complex symptoms of Long COVID through multiple mechanisms such as virus suppression, inflammation suppression, and neuroprotection. We hope that the clinical trial will be successful and provide a practical treatment option for Long COVID patients, which will be historic." About Hyundai Bioscience Hyundai Bioscience is a biotechnology company that develops drugs based on its novel drug delivery system technologies to deliver active ingredients safely and efficiently to targeted areas of the human body. Founded in 2000, Hyundai Bioscience focuses on repurposing or expanding indications of existing drugs using its proprietary organic-inorganic hybrid technologies. Hyundai Bioscience is a public company listed on KOSDAQ (symbol: 048410) in South Korea. For more information, please contact Ms. Joobin Jung, Global PR Manager ([email protected]). SOURCE Hyundai Bioscience WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED