Defined microbial communities to prevent and eradicate infection by AMR pathogens

定义微生物群落以预防和根除 AMR 病原体感染

• 批准号: 10583468
• 负责人: ROBERT A BRITTON
• 金额: $ 56.87万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583468
• 关键词: Accounting; Acute; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Back; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacteriophages; Cause of Death; Cessation of life; Clinical Trials; Clostridium difficile; Communicable Diseases; Communities; Diagnosis; Diet; Disease; Drug resistance; Enterobacteriaceae; Escherichia coli; Escherichia coli Infections; Exposure to; Extended-spectrum β-lactamase; Focal Infection; Goals; Growth; Health Benefit; Hospitals; Human; Human Microbiome; Human body; In Vitro; Individual; Infection; Infection prevention; Inflammation; Intervention; Intestines; Learning; Lytic; Medical Care Costs; Metabolic; Methods; Microbe; Microbial Physiology; Mucous Membrane; Nutritional; Organoids; Outpatients; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Pneumonia; Population Heterogeneity; Predisposition; Prevention strategy; Probiotics; Property; Public Health; Recurrence; Resistance; Risk; Sampling; Site; Surface; Testing; Therapeutic; United States; Urinary tract infection; Uropathogen; Vagina; Virulence; Work; carbapenem resistance; clinically relevant; colonization resistance; combat; commensal bacteria; commensal microbes; design; dysbiosis; environmental change; experimental study; fecal transplantation; gastrointestinal; gut microbiome; gut microbiota; healthcare-associated infections; human microbiota; human tissue; innovation; metabolomics; microbial; microbial community; microbiome; microbiota; mouse model; multi-drug resistant pathogen; novel; opportunistic pathogen; pathobiont; pathogen; pathogenic Escherichia coli; pathogenic bacteria; preservation; pressure; prevent; recurrent infection; success; synergism; tissue culture; transmission process

Project Summary Before the discovery of antibiotics, infectious diseases were the three leading causes of death in the United States and constituted nearly 50% of the deaths annually. Today only one infectious disease, pneumonia, is among the top 10 causes of death in the US, largely due to the success of antibiotics in treating bacterial infections. Unfortunately, the public health benefits provided by antibiotics are at serious risk due to the emergence of antibiotic resistant bacteria, an inevitable consequence of the evolutionary pressure exerted on bacteria by these drugs. Eventually the bacterial pathogens we hope to keep at bay will become resistant to all clinically relevant antibiotics, plunging humans back into a pre-antibiotic world in which infectious disease is the leading cause of death. Therefore, we need to find innovative, and rapidly implementable, ways to reduce or supplement antibiotics to preserve their utility in controlling bacterial infections. Many bacterial pathogens, termed pathobionts, reside within the human microbiota in the absence of disease and only instigate pathogenesis after disruption of the microbial community driven by abrupt environmental changes such as acute inflammation. While there is general acceptance that the commensal microbes provide pathogen colonization resistance and suppression of pathobiont virulence in a healthy state, the mechanistic understanding for how they provide these benefits is lacking. In this project, we explore using the human microbiome to identify ecological principles that allow for the design and implementation of microbial communities that suppress bacterial pathogens. We have selected Clostridioides difficile and extraintestinal pathogenic E. coli (ExPEC) as the two main pathogens to study as they are deemed antibiotic resistance threats by the CDC and necessitate millions of antibiotic prescriptions each year. Even with antibiotic treatment, recurrent infections with both of these pathogens is common, and there is currently a lack of long-lasting preventative strategies. Using a novel method to simplify human microbiome communities and advanced in vitro human tissue culture and humanized murine models, we seek to identify key microbial consortia for suppressing these pathogens. We ultimately expect to optimize a small number of defined microbial communities that can be used to eradicate or prevent these infections in people.

项目概要 在抗生素发现之前，传染病是美国三大死亡原因 州，占每年死亡人数的近 50%。今天，只有一种传染病，即肺炎 跻身美国十大死因之列，很大程度上归功于抗生素治疗细菌的成功 感染。不幸的是，抗生素提供的公共健康益处正面临严重风险，因为 抗生素耐药性细菌的出现，是进化压力的必然结果 这些药物的细菌。最终，我们希望阻止的细菌病原体将对所有病原体产生抗药性 临床相关的抗生素，使人类回到抗生素出现之前的世界，在这个世界中，传染病是主要疾病 死亡的主要原因。因此，我们需要找到创新且可快速实施的方法来减少或 补充抗生素以保持其控制细菌感染的效用。许多细菌性病原体， 称为病原体，在没有疾病的情况下存在于人类微生物群中，并且只会煽动 突然的环境变化（例如急性环境变化）导致微生物群落破坏后的发病机制 炎。虽然人们普遍认为共生微生物提供病原体定植 在健康状态下对致病生物毒力的抵抗和抑制，对如何抵抗和抑制致病生物毒力的机制理解 他们所提供的这些好处是所缺乏的。在这个项目中，我们探索使用人类微生物组来识别 允许设计和实施抑制微生物群落的生态原则 细菌病原体。我们选择了艰难梭菌和肠外致病性大肠杆菌（ExPEC）作为 需要研究的两种主要病原体，因为疾病预防控制中心认为它们具有抗生素耐药性威胁，因此有必要 每年有数百万张抗生素处方。即使采用抗生素治疗，两者都会反复感染 这些病原体很常见，目前缺乏持久的预防策略。使用小说 简化人类微生物群落的方法和先进的体外人体组织培养和人源化 通过鼠模型，我们寻求识别抑制这些病原体的关键微生物群落。我们最终 期望优化少量确定的微生物群落，可用于根除或预防 这些人类感染。