Development of Novel Bacteriophages Targeting Enteric Bacterial Pathogens

针对肠道细菌病原体的新型噬菌体的开发

基本信息

批准号：
10251246
负责人：
Christina S Faherty
金额：
$ 24.93万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251246
关键词：
5 year old Address Age Antibiotic Resistance Antibiotics Antimicrobial Resistance Bacteria Bacteriophages Biological Assay Biology Biomedical Engineering CRISPR/Cas technology Cause of Death Cessation of life Child Clinical Communities Cytolysis DNA Packaging Data Developed Countries Developing Countries Development Diarrhea Disease Outbreaks Engineering Ensure Enteral Environment Epithelial Epithelial Cells Escherichia coli Future Gastrointestinal tract structure Goals Growth and Development function Guide RNA Human Infection Intestines Lead Life Link Malnutrition Mediating Mission Modeling Mucous Membrane Mutagenesis Mutation National Institute of Allergy and Infectious Disease Oral Rehydration Therapy Organoids Pathogenesis Pathogenicity Population Public Health Recurrence Research Resistance Salmonella Sanitation Savings Shigella Specificity System Technology Testing Therapeutic Type III Secretion System Pathway Vaccines Variant Virulence Factors Virus Water Work World Health Organization antibiotic resistant infections antimicrobial resistant pathogen bacterial resistance base clinically relevant combat commensal bacteria comparative genomics cytotoxicity efficacy evaluation emerging pathogen enteric pathogen foodborne foodborne outbreak global health improved infection rate innovation interest microbiome monolayer novel novel therapeutics nuclease particle pathogen pathogenic Escherichia coli pathogenic bacteria pre-clinical preclinical development prevent priority pathogen prototype success synthetic biology targeted nucleases therapeutic development therapeutically effective tool waterborne waterborne outbreak

项目摘要

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

抽象的该R21提案的重点是针对肠细菌病原体的新型治疗剂的发展，特别是志贺氏菌。病原体引起数百万感染和惊人的死亡尽管有干净的水，卫生和口服补液疗法等进展，但每年都在全球范围内。感染是由于细菌侵袭胃肠道的上皮细胞，主要是发生在发展中国家五岁以下儿童中。在工业化国家中，感染是与日托中心，食源和水上爆发有关。尽管进行了数十年的研究，但没有对志贺氏菌的有效疫苗。此外，抗生素耐药性令人震惊治疗。该提案旨在基于最新发现，以发展和评估病原体特异性噬菌体，感染细菌的病毒，用于未来的治疗发育。该项目的长期目标是利用生物工程和合成生物学来开发可用作治疗的新型噬菌体治疗传染性腹泻的选择，而不会损害健康的共生细菌种群胃肠道。该提案的具体目的是首先利用生物工程来增强我们原型噬菌体，随后测试了病原体特异性裂解的增强候选者；第二，进一步设计原型噬菌体以扩大宿主范围并延迟抗噬菌体的出现细菌以绕过天然噬菌体的常见问题。拟议的研究包括使用创新方法，技术和感染模型模仿人类特定环境的环境胃肠道。该提案将由研究团队进一步提高，该研究团队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衍生的感染模型。从目标获得的数据将导致新的治疗剂的发展在猖ramp的抗菌素耐药性和缺乏有效疫苗的时代，临床上有效。 1