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: 10287665
• 负责人: Miriam S. Braunstein
• 金额: $ 23.33万
• 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/10287665
• 关键词: Address; Anti-Bacterial Agents; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacteriophages; Biomedical Research; Bronchiectasis; Chronic Obstructive Airway 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 Transplantation; 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; Pharmaceutical Preparations; Prevalence; Prevention strategy; Principal Investigator; 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抗生素耐药细菌感染的日益增长的问题。 噬菌体（噬菌体）是感染并杀死细菌的病毒。因为噬菌体和抗生素的差异 杀戮机制，噬菌体疗法是​​预防和治疗耐药性的潜在策略 细菌。 耐药性无结枝杆菌（NTM）感染正在增加，它们是一个重大威胁 对于有潜在肺部疾病（例如囊性纤维化（CF），慢性阻塞性肺部疾病）的患者 （COPD）或非CF支气管扩张。脓肿分枝杆菌是遇到的最常见的NTM 在肺NTM疾病中，这是最难治疗的。 M.腹肌具有极高的耐药性，并且 没有系统证明的方案有效。噬菌体疗法，涉及三个鸡尾酒 分枝杆菌（分枝杆菌）最近在富有同情心的情况下雇用 在CF患者中传播了脓肿的分枝杆菌疾病。这种霉菌治疗与临床有关 改善患者。但是，患者的脓肿感染尚未完全解决和 两年后，每天两次用静脉内噬细胞进行治疗。正在进行的局限 霉菌治疗尚不清楚。 噬菌体疗法知识的显着差距是噬菌体是否可以与其宿主细菌相互作用 感染期间遇到的不同微环境。 M. abcessus能够在细胞内生存 巨噬细胞和细胞外生物膜。霉菌是否可以在这些中杀死M. abcessus 环境未知。菌噬细胞在正常粘液或病理CF中遍历和起作用的能力 粘液也是未知的。使用一系列腹部分离株和分枝杆菌，包括 从正在进行的临床病例中，我们将评估这些潜在障碍（巨噬细胞，，， 生物膜和粘液）对菌根活性。这些研究的结果将阐明微环境 这可能会特别限制M. Abscessus的噬菌体活动，更广泛地说明潜在的挑战 细胞内，生物膜形成和肺细菌病原体的噬菌体治疗。我们期望知识 获得的将推动制定改善噬菌体疗法的策略，以预防和治疗药物 抗性细菌感染。鉴于需要治疗腹部大肠杆菌的疗法，该R21对 不是-AI-17-016（NIAID对与肺非辅助，肺非辅助研究的生物医学研究的兴趣 结核分枝杆菌（NTM）感染）。