Development of therapeutic bacteriophages against carbapenemase-resistant Klebsiella pneumoniae

 描述（由申请人提供）：对多种广泛类别的抗生素具有耐药性的细菌菌株的持续出现引起了医学界的严重关注，一些人甚至认为我们可能即将进入“后抗生素时代”。在耐药细菌中，产碳青霉烯酶的肠杆菌科成员，特别是携带blaKPC等位基因的肺炎克雷伯菌，是最令人担忧的病原体。噬菌体，感染细菌的病毒，已被提议作为用于治疗这些MDR细菌感染的生物控制剂。噬菌体具有特异性、无毒和能够在细菌感染部位生长的优点，并且已经在动物模型研究中显示出治愈多种细菌感染。然而，关于体内噬菌体功效的原理知之甚少。本项目中提出的工作将组装一个能够杀死KPC+ K的裂解酶的良好表征的文库。pneumoniae分离株，并开发无症状KPC+ K的小鼠和兔模型。KPC+ K.肺炎。库中的宿主范围、耐药性特征、生长特征和体内性能将用于组装对广泛的临床相关KPC+ K具有最大疗效的KPC混合物。pneumoniae菌株，并将在为本研究开发的小鼠和兔感染模型中评价这些菌株。这项工作将产生一种基于噬菌体的治疗剂，将直接应用于KPC+ K的治疗。本发明的目的是研究人肺炎杆菌感染，并将确定与体内功效相关的一些噬菌体参数。

 DESCRIPTION (provided by applicant): The continued emergence of bacterial strains that are resistant to multiple broad classes of antibiotics has raised significant concern among the medical community, some even suggesting we may be about to enter a "post-antibiotic era". Among resistant bacteria, carbapenemase-producing members of the Enterobacteriaceae, particularly Klebsiella pneumoniae carrying the blaKPC allele, are agents of major concern. Bacteriophages, viruses that infect bacteria, have been proposed as biological control agents for the treatment of these MDR bacterial infections. Phages have the advantages of being specific, non-toxic and capable of growing at the site of the bacterial infection, and have been shown to cure a wide variety of bacterial infections in animal model studies. However, little is understood regarding the principles of in vivo phage efficacy. The work proposed in this project will assemble a well-characterized library of lytic phages capable of killing KPC+ K. pneumoniae isolates, and develop mouse and rabbit models of asymptomatic KPC+ K. pneumoniae carriage and gut-derived bacteremia caused by KPC+ K. pneumoniae. The host ranges, resistance profiles, growth characteristics and in vivo performance of the phages in the library will be used to assemble a mixture of phages with maximal efficacy against a broad swath of clinically relevant KPC+ K. pneumoniae strains, and these will be evaluated in mouse and rabbit models of infection developed for this study. This work will produce a phage-based therapeutic that will have a direct application for treatment of KPC+ K. pneumoniae infection in humans, and will determine some of the phage parameters associated with in vivo efficacy.