A Bio-controlled, Microbiota-Sparing, Live Biotherapeutic Anti-Infective for Clostridioides difficile

一种针对艰难梭菌的生物控制、保留微生物群的活生物治疗抗感染药物

• 批准号: 10586070
• 负责人: Gayatri Vedantam
• 金额: $ 18.49万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-07 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586070
• 关键词: Address; Adherence; Animal Model; Anti-Infective Agents; Antibiotics; Antibodies; Antigens; Bacteria; Bacterial Adhesins; Bacterial Infections; Biocontrols; Biological; Biological Response Modifier Therapy; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Clinical Trials; Clostridium difficile; Diarrhea; Disease; Dose; Drug Kinetics; Engineering; Epithelial Cells; Exploratory/Developmental Grant; Expression Profiling; FDA approved; Funding; Futility; Goals; Hamsters; Healthcare; Human; Immune response; Immunity; In Vitro; Infection; Intoxication; Laboratories; Lactobacillus casei; Licensing; Life; Literature; Mediating; Medical; Mesocricetus auratus; Metabolic; New Agents; Patients; Phase III Clinical Trials; Phylogenetic Analysis; Preclinical Testing; Preventive; Primary Prevention; Property; Proteins; Publishing; Recurrence; Reporting; Research; Risk; Rodent; Rodent Model; Surface; Technology; Testing; Toxin; Toxoids; United States National Institutes of Health; Vaccines; Validation; adaptive immunity; adverse outcome; bacterial resistance; colonization resistance; community setting; cytotoxicity; dysbiosis; fecal transplantation; gut dysbiosis; health care settings; high risk; immunogenic; intestinal epithelium; lactic acid bacteria; microbiota; novel; oral vaccine; pathogen; preclinical study; prevent; receptor binding; recurrent infection; response; restoration; vaccine candidate

Abstract Clostridioides difficile can cause life-threatening diarrhea, and C. difficile Infections (CDIs) typically occur in patients who have been administered antibiotics. CDI is dominant in both healthcare and community settings, with >500,000 cases annually in the USA. The CDC designated C. difficile as one of five `Urgent Threats' to US healthcare in 2013, and again in 2019. Currently, antibiotics are the only fully FDA-approved treatment for CDI. The persistent dysbiosis induced by antibiotics, however, can contribute to recurrent infections in a significant proportion of patients. Microbiota restoration via fecal transplants (FMT) can be highly effective against recurrent CDI, but have also been associated with adverse outcomes, including death. There are no licensed vaccines to prevent CDIs. In 2020, it was reported that a large Phase III Clinical Trial of a vaccine based on the C. difficile toxins met the criteria for futility and that the study was terminated. To date, all C. difficile vaccine candidates in late-stage clinical trials continue to be based solely on the toxins. Herein, we propose to systematically refine a synthetic bacterium that we recently developed and tested. The new anti-infective agent will prevent CDI in a strain-agnostic and multi-pronged manner highlighted by niche occupancy (colonization resistance) as well as adaptive immunity (oral vaccine) against the pathogen and its toxins. In Aim 1, we will build key metabolic and new antigen-display features into the existing bacterial platform, and characterize it in vitro. Aim 2 studies will employ two rodent models to assess the ability of the anti-infective agent to prevent both primary and recurrent CDI. Given that biocontrol and immunity features will require validation before other in-depth pre-clinical testing, we propose the “high-risk/high-payoff” R21 mechanism for this project. Our approach builds on prior NIH-funded research in our laboratory, and focuses on a safer alternative to FMT. Further, and via the built-in precision viability that we will engineer, our technology will not engender the extensive dysbiosis attendant with antibiotic use. The long-term impact of this effort may therefore be realized via deployment of this novel anti-infective for all at-risk patients (not just those with recurrent CDI).

摘要 艰难梭菌可引起危及生命的腹泻，而C。艰难梭菌感染（CDIs）通常发生在 使用过抗生素的患者。CDI在医疗保健和社区环境中都占主导地位， 在美国每年有超过500，000例。疾病预防控制中心将C.作为对美国的五个“紧急威胁”之一， 2013年的医疗保健，以及2019年的医疗保健。 目前，抗生素是FDA唯一完全批准的CDI治疗方法。持续的生态失调 然而，抗生素可导致相当大比例的患者的复发性感染。菌群 通过粪便移植（FMT）恢复可以非常有效地对抗复发性CDI，但也被认为是一种有效的治疗方法。 与不良后果相关，包括死亡。 目前还没有获得许可的疫苗来预防CDIs。2020年，据报道，一项大型III期临床试验 以C.艰难梭菌毒素符合无效标准，研究终止。迄今为止，所有 C.在后期临床试验中的艰难梭菌候选疫苗仍然仅仅基于毒素。 在这里，我们建议系统地改进我们最近开发和测试的合成细菌。的 一种新的抗感染药物将以一种不依赖于菌株的多管齐下的方式预防CDI， 占领（定植抗性）以及适应性免疫（口服疫苗）对病原体及其 毒素在目标1中，我们将在现有的细菌平台中构建关键的代谢和新的抗原展示特征， 并在体外对其进行表征。目的2研究将采用两种啮齿动物模型来评估抗感染的能力 预防原发性和复发性CDI的药物。鉴于生物控制和免疫功能将需要 在其他深入的临床前测试之前，我们提出了“高风险/高回报”R21机制， 这个项目 我们的方法建立在我们实验室先前NIH资助的研究基础上，并专注于FMT的更安全替代品。 此外，通过我们将设计的内置精确可行性，我们的技术将不会产生广泛的 抗生素使用导致的生态失调。因此，这一努力的长期影响可以通过以下方式实现： 这种新型抗感染药物的部署适用于所有高危患者（不仅仅是那些复发性CDI患者）。

项目成果

Prevalence of diagnostically-discrepant Clostridioides difficile clinical specimens: insights from longitudinal surveillance.

• DOI: 10.3389/fmed.2023.1238159
• 发表时间: 2023
• 期刊: FRONTIERS IN MEDICINE
• 影响因子: 3.9
• 作者: Anwar, Farhan;Clark, Marielle;Lindsey, Jason;Claus-Walker, Rachel;Mansoor, Asad;Nguyen, Evy;Billy, Justin;Lainhart, William;Shehab, Kareem;Viswanathan, V. K.;Vedantam, Gayatri
• 通讯作者: Vedantam, Gayatri