Pyocins as antibacterials to treat Pseudomonas aeruginosa infections

项目摘要/摘要。 铜绿假单胞菌是一种自然耐药的细菌病原体，可引起严重和致命的 急性和慢性感染，特别是受感染的个人。需要新的疗法来治疗这种 感染，如铜绿假单胞菌通常对常用抗生素具有耐药性。最近，噬菌体疗法已经 作为治疗铜绿假单胞菌引起的感染的一种方法重新出现。噬菌体的优势在于它们 可以特异性地裂解目标细菌。然而，噬菌体可以复制并潜在地转移遗传物质。 包括从一种细菌到另一种细菌的抗生素耐药性或毒力基因。我们建议用噬菌体代替噬菌体 测试细菌素，R-腐菌素，作为治疗铜绿假单胞菌感染的药物的疗效。 细菌素是细菌产生的对同一物种具有活性的抗菌素。R-吡咯菌素 是由铜绿假单胞菌产生的，与P2噬菌体的收缩尾巴有关，但缺乏 噬菌体头部结构，没有核酸，因此不能复制。R-品红可分为三类 根据与铜绿假单胞菌上特定位点的结合而不同的亚型(R1、R2和R5) 脂多糖结构。尽管R-腐霉素在体外对许多铜绿假单胞菌有明显的疗效， 在小鼠感染模型中验证R-腐殖素的研究相对较少，而且只有一种 已发表的研究报告使用了一种肺部感染的小鼠模型。这个新的美国国立卫生研究院的目标是 探索/发展研究资助奖(R21资助奖)是为了评估铜绿假单胞菌对R- 在模拟肺环境的体外条件下以及在急性小鼠呼吸模型中的腐殖素 感染的可能性。我们推测，在这种与感染更相关的生长过程中，R-腐殖素敏感性测试 环境将提供更好的真实敏感性的指示，体内更多的分离株将提供 进一步考虑将R-脓毒菌素作为治疗药物的迫切需要的理由。

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.