Effect of Microenvironment on the Activity of Mycobacteriophages for Treating Mycobacterium abscessus

微环境对治疗脓肿分枝杆菌噬菌体活性的影响

• 批准号: 10454361
• 负责人: Miriam S. Braunstein
• 金额: $ 19.44万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454361
• 关键词: Address; Anti-Bacterial Agents; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacteriophages; Biomedical Research; Bronchiectasis; Chronic Obstructive Pulmonary Disease; Clinical; Collection; Cystic Fibrosis; Development; Diffuse; Diffusion; Disease; Drug resistance; Engineering; Environment; Genus Mycobacterium; Human; Hydration status; Individual; Infection; Intravenous; Knowledge; Letters; Light; Lung; Lung diseases; Lung infections; Measures; Methods; Microbial Biofilms; Morbidity - disease rate; Mucins; Mucous body substance; Mycobacteriophages; Mycobacterium Infections; Mycobacterium abscessus; National Institute of Allergy and Infectious Disease; Pathologic; Patients; Penetration; Persons; Pharmaceutical Preparations; Prevalence; Prevention strategy; Principal Investigator; Pulmonary Cystic Fibrosis; Regimen; Research Personnel; System; Testing; Transplant Recipients; Virus; Work; biophysical properties; bronchial epithelium; cystic fibrosis mucus; cystic fibrosis patients; disulfide bond; drug resistant bacteria; experience; extracellular; improved; interest; macrophage; monomer; mortality; mycobacterial; non-tuberculosis mycobacteria; novel therapeutics; pathogenic bacteria; patient population; prevent; pulmonary function decline

Novel therapies are needed to control the growing problem of antibiotic-resistant bacterial infections. Bacteriophages (phages) are viruses that infect and kill bacteria. Because phages and antibiotics differ in their killing mechanisms, phage therapy is a potential strategy for prevention and treatment of drug resistant bacteria. Drug resistant nontuberculous mycobacteria (NTM) infections are on the rise and they are a significant threat for people with underlying lung diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) or non-CF bronchiectasis. Mycobacterium abscessus is one of the most common NTMs encountered in pulmonary NTM disease and it is the most difficult to treat. M. abscessus is extremely drug resistant and there is no systematically proven regimen that is effective. Phage therapy, involving a cocktail of three mycobacteriophages (mycophages), was recently employed under compassionate use conditions to treat disseminated M. abscessus disease in a CF patient. This mycophage treatment was associated with clinical improvement of the patient. However, the M. abscessus infection of the patient has yet to fully resolve and twice-daily treatment with intravenous mycophages is ongoing two years later. The limitations of the ongoing mycophage treatment are unknown. A significant gap in knowledge for phage therapy is whether phages can interact with their host bacteria in the different microenvironments encountered during infection. M. abscessus is able to both survive intracellularly in macrophages and extracellularly in biofilms. Whether mycophages can kill M. abscessus in these environments is unknown. The ability of mycophages to traverse and act in normal mucus or pathological CF mucus is also unknown. Working with a collection of M. abscessus isolates and mycophages, including those from the ongoing clinical case, we will evaluate the impact of each of these potential barriers (macrophages, biofilms, and mucus) on mycophage activity. The results of these studies will shed light on microenvironments that may limit phage activity for M. abscessus specifically and, more broadly, inform on potential challenges to phage therapy for intracellular, biofilm forming, and pulmonary bacterial pathogens. We expect the knowledge gained will drive development of strategies to improve phage therapy as an option to prevent and treat drug resistant bacterial infections. Given the need for therapies to treat M. abscessus, this R21 is responsive to NOT-AI-17-016 (Notice of NIAID’s Interest in Biomedical Research in non-AIDS associated, Pulmonary Non- Tuberculous Mycobacterial (NTM) Infections).

需要新的疗法来控制日益严重的耐药性细菌感染问题。 噬菌体（Bacteriophage，简写为BPHs）是一种能够感染并杀死细菌的病毒。因为抗生素和抗生素的不同之处在于， 噬菌体治疗是一种潜在的防治耐药的策略， 细菌 耐药非结核分枝杆菌（NTM）感染呈上升趋势，是一个重大威胁 对于患有潜在肺部疾病的人，如囊性纤维化（CF），慢性阻塞性肺病 （COPD）或非CF支气管扩张。结核分枝杆菌是最常见的非结核分枝杆菌之一 在肺NTM疾病中，它是最难治疗的。Pestiessus具有极强的抗药性， 没有系统地证明有效的方案。噬菌体疗法，包括三种混合物 分枝杆菌噬菌体（mycophages），最近在同情使用条件下被用于治疗 散布型M. CF患者中的肌纤维化疾病。这种噬菌体治疗与临床 患者的改善。然而，M.患者的尿道感染尚未完全解决， 两年后，每天两次静脉注射噬菌体进行治疗。正在进行的限制 真菌噬菌体治疗是未知的。 噬菌体治疗知识的一个重大空白是噬菌体是否能与宿主细菌相互作用， 感染时遇到的不同微环境。M. Escheressus既能在细胞内存活， 巨噬细胞和细胞外的生物膜。噬菌体是否能杀死M.在这些企业 环境未知。噬菌体在正常粘液或病理性CF中穿过和作用的能力 粘液也是未知的。使用M的集合。真菌分离物和噬菌体，包括那些 从正在进行的临床病例中，我们将评估这些潜在屏障中的每一个的影响（巨噬细胞， 生物膜和粘液）对噬菌体活性的影响。这些研究的结果将揭示微环境 这可能会限制M的噬菌体活性。具体而言，并在更广泛的范围内，告知潜在的挑战， 用于细胞内、生物膜形成和肺部细菌病原体的噬菌体疗法。我们期待知识 获得的将推动发展战略，以改善噬菌体治疗作为一种选择，以预防和治疗药物 耐药细菌感染。考虑到治疗M.这辆R21对 NOT-AI-17-016（NIAID对非艾滋病相关、非肺疾病的生物医学研究的兴趣通知） 结核分枝杆菌（NTM）感染）。