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).

抽象的 艰难梭菌可引起危及生命的腹泻，艰难梭菌感染 (CDI) 通常发生在 接受过抗生素治疗的患者。 CDI 在医疗保健和社区环境中均占主导地位， 美国每年有超过 500,000 例病例。疾病预防控制中心将艰难梭菌列为美国的五个“紧急威胁”之一 2013 年和 2019 年的医疗保健。 目前，抗生素是唯一获得 FDA 完全批准的 CDI 治疗方法。引起的持续性菌群失调 然而，抗生素可能会导致很大一部分患者反复感染。微生物群 通过粪便移植 (FMT) 进行恢复对于复发性 CDI 非常有效，但也 与不良后果（包括死亡）相关。 目前还没有获得许可的疫苗可以预防 CDI。 2020年，据报道一项大型III期临床试验 基于艰难梭菌毒素的疫苗符合无效标准，因此研究终止。迄今为止，所有 处于后期临床试验中的艰难梭菌候选疫苗仍然仅基于毒素。 在此，我们建议系统地改进我们最近开发和测试的合成细菌。这 新型抗感染药物将以与菌株无关和多管齐下的方式预防 CDI，利基强调 占领（定植抗性）以及针对病原体及其病原体的适应性免疫（口服疫苗） 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功能， 并在体外对其进行表征。目标 2 研究将采用两种啮齿动物模型来评估该药物的抗感染能力 预防原发性和复发性 CDI 的药物。鉴于生物防治和免疫功能需要 在其他深入的临床前测试之前进行验证，我们提出了“高风险/高回报”的 R21 机制 这个项目。 我们的方法建立在我们实验室先前由 NIH 资助的研究基础上，并专注于 FMT 的更安全替代方案。 此外，通过我们将设计的内置精确可行性，我们的技术不会产生广泛的 抗生素的使用会导致菌群失调。因此，这一努力的长期影响可以通过以下方式实现： 对所有高危患者（不仅仅是那些患有复发性 CDI 的患者）使用这种新型抗感染药物。

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