Pyocins as antibacterials to treat Pseudomonas aeruginosa infections

脓毒素作为抗菌药物治疗铜绿假单胞菌感染

• 批准号: 10727705
• 负责人: Joanna B Goldberg
• 金额: $ 21.99万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727705
• 关键词: Acute; Acute Pneumonia; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Award; Bacteremia; Bacteria; Bacterial Antibiotic Resistance; Bacteriophages; Binding; Biological Assay; Cessation of life; Chemicals; Chronic; Cystic Fibrosis sputum; Development; Environment; Gene Expression; Genetic Materials; Goals; Grant; Growth; Head; Hour; In Vitro; Individual; Infection; Laboratories; Life; Lipopolysaccharides; Lung; Lung infections; Lytic; Methods; Modeling; Multi-Drug Resistance; Mus; Nosocomial Infections; Nosocomial pneumonia; Nucleic Acids; Nutritional; O Antigens; Patients; Pneumonia; Predisposition; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Publishing; Pulmonary Cystic Fibrosis; Reporting; Research Personnel; Research Project Grants; Resistance; Serotyping; Site; Spottings; Structure; Tail; Testing; Therapeutic; Therapeutic Agents; Translating; United States National Institutes of Health; acute infection; antimicrobial; bacteriocin; chronic infection; cystic fibrosis infection; cystic fibrosis patients; efficacy testing; hospital care; improved; in vivo; mouse model; novel therapeutics; opportunistic pathogen; pathogen; pathogenic bacteria; pneumonia model; priority pathogen; resistance gene; respiratory; validation studies; virulence gene

PROJECT SUMMARY/ABSTRACT. Pseudomonas aeruginosa is a naturally antibiotic resistant bacterial pathogen that causes severe and deadly acute and chronic infections, particularly in compromised individuals. New therapeutics are needed to treat such infections, as P. aeruginosa is often resistant to commonly used antibiotics. Recently, phage therapy has reemerged as an approach to treat infections caused by P. aeruginosa. The advantage of phages is that they can specifically lyse target bacteria. However, phages replicate and can potentially transfer genetic material including antibiotic resistance or virulence genes from one bacterium to another. Instead of phages, we propose to test the efficacy of the bacteriocins, R-pyocins, as therapeutic agents to treat P. aeruginosa infections. Bacteriocins are antimicrobials produced by a bacterium that are active against the same species. R-pyocins are specifically produced by P. aeruginosa and are related to the contractile tail of P2 bacteriophages, but lack the phage head structure, have no nucleic acids, and thus cannot replicate. R-pyocins can be grouped into three subtypes (R1, R2, and R5) that differ based on their binding to specific sites on the P. aeruginosa lipopolysaccharide structure. Despite the apparent efficacy of R-pyocins against many P. aeruginosa in vitro, there have been relatively few studies validating R-pyocins in mouse models of infection and only a single published study has been reported using a murine model of lung infection. The goal of this new NIH Exploratory/Developmental Research Grant Award (R21 Grant) is to assess P. aeruginosa susceptibility to R- pyocins under in vitro conditions that mimic the lung environment and also in an acute mouse respiratory model of infection. We hypothesize that R-pyocin susceptibility testing in this more infection-relevant growth environment will provide a better indication of true susceptibility and testing additional isolates in vivo will provide the much-needed justification for further consideration of R-pyocins as therapeutics agents.

项目总结/摘要。 铜绿假单胞菌是一种天然的抗生素耐药性细菌病原体， 急性和慢性感染，特别是在受损的个体中。需要新的疗法来治疗这种疾病。 感染，因为铜绿假单胞菌通常对常用的抗生素具有耐药性。最近，噬菌体疗法 作为治疗由铜绿假单胞菌引起的感染的方法再次出现。但它的优点是， 能特异性裂解目标细菌。然而，DNA复制并可能转移遗传物质， 包括从一种细菌到另一种细菌的抗生素抗性或毒力基因。我们建议不使用噬菌体， 测试细菌素R-绿脓菌素作为治疗铜绿假单胞菌感染的治疗剂的功效。 细菌素是由细菌产生的抗微生物剂，对相同的物种具有活性。绿脓菌素 由铜绿假单胞菌特异性产生，与P2噬菌体的收缩尾相关，但缺乏 噬菌体头部结构没有核酸，因此不能复制。R-绿脓菌素可以分为三种 亚型（R1、R2和R5）根据其与铜绿假单胞菌上特定位点的结合而不同 脂多糖结构。尽管R-绿脓菌素在体外对许多铜绿假单胞菌具有明显的功效， 在小鼠感染模型中验证R-绿脓菌素的研究相对较少， 已发表的研究报告使用肺部感染的鼠模型。这个新的NIH的目标是 探索性/发展性研究资助奖（R21 Grant）旨在评估铜绿假单胞菌对R- 绿脓菌素在模拟肺环境的体外条件下以及在急性小鼠呼吸模型中 感染我们推测，在这种与感染相关性更强的生长中， 环境将提供更好的真实敏感性指示，并在体内测试额外的分离株将提供 进一步考虑R-绿脓菌素作为治疗剂的迫切需要的理由。