Development of therapeutic bacteriophages against carbapenemase-resistant Klebsiella pneumoniae

开发针对耐碳青霉烯酶肺炎克雷伯菌的治疗性噬菌体

• 批准号: 9198199
• 负责人: Jason J. Gill
• 金额: $ 23.59万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-22 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198199
• 关键词: Alleles; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteremia; Bacteria; Bacterial Infections; Bacteriophages; Biological; Burkholderia; Cessation of life; Characteristics; Chemicals; Clinical; Collection; Communities; Conduct Clinical Trials; Critical Illness; Development; Drug resistance; Enterobacteriaceae; Environment; Food; Gastrointestinal tract structure; Goals; Gram-Negative Bacteria; Growth; Human; Immunocompromised Host; Individual; Infection; Intravenous; Klebsiella pneumonia bacterium; Lead; Libraries; Life Cycle Stages; Lytic; Medical; Medicine; Modeling; Mus; National Institute of Allergy and Infectious Disease; Oral; Organism; Oryctolagus cuniculus; Outcome; Patients; Performance; Personal Communication; Pseudomonas aeruginosa; Public Health; Research; Resistance; Resistance profile; Risk; Sepsis; Site; Soil; Study models; Surface; Testing; Therapeutic; Treatment Efficacy; United States National Institutes of Health; Uropathogenic E. coli; Virulent; Virus; Water; Work; antimicrobial; antimicrobial drug; bacterial resistance; bactericide; base; carbapenemase; clinically relevant; combat; design; direct application; effective therapy; experience; gastrointestinal; in vivo; killings; member; mouse model; pathogen; prevent; public health relevance; receptor; resistant strain; small molecule; therapeutic development; treatment strategy

 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.

 描述(由申请人提供)：对多种抗生素具有抗药性的细菌菌株的持续出现引起了医学界的极大关注，一些人甚至暗示我们可能即将进入“抗生素后时代”。在耐药细菌中，肠杆菌科的碳青霉烯酶产生菌，特别是携带blaKPC等位基因的肺炎克雷伯菌，是主要的关注因素。噬菌体是一种感染细菌的病毒，已被建议用作治疗这些多药耐药细菌感染的生防剂。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，在动物模型研究中已被证明可以治愈各种细菌感染。然而，对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具有良好特性的能够杀死KPC+肺炎克雷伯菌分离株的裂解噬菌体文库，并建立无症状KPC+肺炎克雷伯菌携带者和由KPC+肺炎克雷伯菌引起的肠源性菌血症的小鼠和兔模型。文库中噬菌体的宿主范围、耐药性、生长特性和体内表现将被用来组装对广泛的临床相关KPC+肺炎克雷伯菌菌株具有最大效力的噬菌体混合物，并将在为本研究开发的小鼠和兔感染模型中进行评估。这项工作将产生一种基于噬菌体的治疗方法，将直接应用于治疗人类KPC+肺炎克雷伯菌感染，并将确定与体内疗效相关的一些噬菌体参数。

项目成果

Complete Genome Sequence of Klebsiella pneumoniae Jumbo Phage Miami.

• DOI: 10.1128/mra.01404-20
• 发表时间: 2021-01-28
• 期刊: Microbiology resource announcements
• 影响因子: 0.8
• 作者: Mora D;Lessor L;Le T;Clark J;Gill JJ;Liu M
• 通讯作者: Liu M

Complete Genome Sequence of Klebsiella pneumoniae Myophage May.

肺炎克雷伯菌肌噬菌体的完整基因组序列

• DOI: 10.1128/mra.00252-19
• 发表时间: 2019
• 期刊: Microbiology resource announcements
• 影响因子: 0.8
• 作者: Nguyen,KatherineT;Bonasera,Rachele;Benson,Garret;Hernandez-Morales,AdrianaC;Gill,JasonJ;Liu,Mei
• 通讯作者: Liu,Mei

Complete Genome Sequence of Klebsiella pneumoniae Myophage Menlow.

肺炎克雷伯菌 Menlow 肌噬菌体的完整基因组序列。

• DOI: 10.1128/mra.00192-19
• 发表时间: 2019
• 期刊: Microbiology resource announcements
• 影响因子: 0.8
• 作者: Newkirk,HeatherN;Lessor,Lauren;Gill,JasonJ;Liu,Mei
• 通讯作者: Liu,Mei

Complete Genome Sequence of Shelby, a Siphophage Infecting Carbapenemase-Producing Klebsiella pneumoniae.

谢尔比（一种感染产碳青霉烯酶肺炎克雷伯菌的噬菌体）的完整基因组序列。

• DOI: 10.1128/mra.01037-19
• 发表时间: 2019
• 期刊: Microbiology resource announcements
• 影响因子: 0.8
• 作者: Saldana,Robert;Newkirk,Heather;Liu,Mei;Gill,JasonJ;Ramsey,Jolene
• 通讯作者: Ramsey,Jolene

Complete Genome Sequence of Klebsiella pneumoniae Myophage Mulock.

肺炎克雷伯菌肌噬菌体 Mulock 的完整基因组序列。

• DOI: 10.1128/mra.01338-19
• 发表时间: 2019
• 期刊: Microbiology resource announcements
• 影响因子: 0.8
• 作者: Min,Lorna;Lessor,Lauren;O'Leary,Chandler;Bonasera,Rachele;Gill,Jason;Liu,Mei
• 通讯作者: Liu,Mei