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.

项目摘要/摘要。 铜绿假单胞菌是一种天然具有抗生素抗性的细菌病原体，可导致严重和致命的疾病 急性和慢性感染，尤其是受影响的个体。需要新的疗法来治疗这种情况 感染，因为铜绿假单胞菌通常对常用抗生素具有耐药性。近年来，噬菌体疗法 作为治疗铜绿假单胞菌引起的感染的方法重新出现。噬菌体的优点是 可以特异性裂解目标细菌。然而，噬菌体复制并有可能转移遗传物质 包括从一种细菌到另一种细菌的抗生素抗性或毒力基因。我们建议代替噬菌体 测试细菌素 R-pyocins 作为治疗药物治疗铜绿假单胞菌感染的功效。 细菌素是由细菌产生的抗菌剂，对同一物种具有活性。 R-化脓菌素 由铜绿假单胞菌特异产生，与 P2 噬菌体的收缩尾部相关，但缺乏 噬菌体头部结构，没有核酸，因此不能复制。 R-pyocins 可分为三类 亚型（R1、R2 和 R5）的不同之处在于它们与铜绿假单胞菌上特定位点的结合 脂多糖结构。尽管 R-pyocins 在体外对许多铜绿假单胞菌具有明显功效， 在小鼠感染模型中验证 R-pyocins 的研究相对较少，而且只有一项研究 已发表的研究报告使用了小鼠肺部感染模型。这个新的 NIH 的目标 探索性/发展性研究补助金（R21 补助金）旨在评估铜绿假单胞菌对 R- 的敏感性 模拟肺环境的体外条件下以及急性小鼠呼吸模型中的脓毒症 的感染。我们假设 R-pyocin 敏感性测试在这种与感染相关的生长中 环境将提供更好的真实敏感性指示，并且体内测试其他分离株将提供 这是进一步考虑 R-脓毒素作为治疗剂所急需的理由。