Development of Novel Bacteriophages Targeting Enteric Bacterial Pathogens

摘要 这项R21提案的重点是开发针对肠道细菌病原体的新疗法， 尤其是志贺氏菌这些病原体导致数百万人感染，死亡人数惊人 尽管有了清洁水、卫生设施和口服补液疗法等进步，但每年仍有地球仪在全球范围内发生。 感染是由于细菌侵入胃肠道的上皮细胞， 发生在发展中国家五岁以下的儿童身上。在工业化国家， 与日托中心、食源性和水源性疫情有关。尽管经过几十年的研究， 志贺氏菌的有效疫苗。此外，抗生素耐药性的惊人增加使 治疗这项建议旨在建立在最近的研究结果，以开发和评估病原体特异性 噬菌体，感染细菌的病毒，用于未来的治疗发展。这个项目的长期目标是 是利用生物工程和合成生物学来开发新的噬菌体， 选择治疗感染性腹泻，而不损害健康的肠道细菌种群， 胃肠道这项建议的具体目标是，首先，利用生物工程来提高我们的 原型噬菌体并随后测试用于病原体特异性裂解的增强的候选物;以及第二， 进一步改造原型噬菌体以扩大宿主范围并延迟噬菌体抗性的出现 细菌来规避天然噬菌体的常见问题。拟议的研究包括使用 创新的方法，技术和感染模型，模仿人类特定的环境， 胃肠道该提案得到了一个研究小组的进一步加强，该研究小组结合了 噬菌体生物学、生物工程、细菌发病机理和粘膜生物学，以及类器官来源的 感染模型从aims获得的数据将导致新疗法的开发， 在抗生素耐药性猖獗和缺乏有效疫苗的时代， 1

Abstract This R21 proposal focuses on the development of novel therapeutics against enteric bacterial pathogens, specifically the Shigella species. The pathogens cause millions of infections and a staggering number of deaths around the globe each year despite advances such as clean water, sanitation, and oral rehydration therapy. Infection is due to bacterial invasion of the epithelial cells lining the gastrointestinal tract, and predominately occurs in children under the age of five years in developing countries. In industrialized nations, infections are linked to daycare center, foodborne, and waterborne outbreaks. Despite decades of research, there are no effective vaccines against Shigella. Furthermore, alarming increases in antibiotic resistance have complicated treatment. This proposal seeks to build upon recent findings to develop and evaluate pathogen-specific bacteriophages, viruses that infect bacteria, for future therapeutic development. The long-term goal of this project is to utilize bioengineering and synthetic biology to develop novel bacteriophages that can be used as therapeutic options to treat infectious diarrhea without harming the healthy commensal bacterial population of the gastrointestinal tract. The specific aims of this proposal are to first, utilize bioengineering to enhance our prototype bacteriophage and subsequently test the enhanced candidate for pathogen-specific lysis; and second, further engineer the prototype phage to expand the host range and delay the emergence of phage-resistant bacteria to circumvent common issues with natural bacteriophages. The proposed research includes the use of innovative approaches, technologies, and infection models that mimic the human-specific environment of the gastrointestinal tract. The proposal is further enhanced by a research team that combines the expertise of bacteriophage biology, bioengineering, bacterial pathogenesis, and mucosal biology, and organoid-derived infection models. Data obtained from the aims will lead to the development of novel therapeutics that could prove to be clinically effective in an age of rampant antimicrobial resistance and a lack of effective vaccines. 1