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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

摘要