The Role of Atypical Cell Wall Biology of Mycobacterium abscessus in Pulmonary Infection and Therapy

脓肿分枝杆菌非典型细胞壁生物学在肺部感染和治疗中的作用

• 批准号: 9756771
• 负责人: Emily Maggioncalda
• 金额: $ 4.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-19 至 2022-03-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756771
• 关键词: Acute; Affect; American; Americas; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Biological; Biology; Bronchiectasis; Caucasians; Cell Wall; Cell physiology; Cells; Chemicals; Chemotherapy-Oncologic Procedure; Chest; Chronic; Communicable Diseases; Cysteine; Cystic Fibrosis; Data; Disease; Drug usage; Enzymes; Glycopeptides; Gram-Positive Bacteria; Granuloma; Growth; Human; Immune; Impairment; Incidence; Individual; Infection; Knowledge; Laboratories; Lead; Life; Lung; Lung infections; Metabolism; Modeling; Monobactams; Mus; Mycobacterium abscessus; Normal Cell; Organism; Pathogenesis; Pathologic; Pathology; Patients; Peptide Hydrolases; Peptides; Peptidoglycan; Peptidyltransferase; Phase; Phenotype; Physiology; Postmenopause; Prevalence; Publishing; Regimen; Resistance; Resort; Role; Series; Serine; Societies; Specificity; Sputum; Stress; Structure; Treatment Efficacy; Treatment Protocols; Woman; Work; base; beta-Lactams; chronic infection; cystic fibrosis patients; exoskeleton; immunosuppressed; improved; in vivo; insight; mouse model; mycobacterial; novel; novel therapeutics; pathogen; side effect; stem; therapeutic development; treatment strategy

PROJECT SUMMARY Patients with structural lung conditions, such as cystic fibrosis and bronchiectasis are highly susceptible to infections with Mycobacterium abscessus. These pathogens are detected in the sputum of ~13% of cystic fibrosis patients in the US. In addition to those with underlying lung conditions, immune competent post-menopausal Caucasian women are also selectively susceptible to pulmonary M. abscessus infections. Despite increasing prevalence of this disease, very little is known about the pathogenesis of pulmonary infections with M. abscessus. This proposal’s aim is to fill critical gaps in our understanding of pulmonary M. abscessus infection. Recent studies have demonstrated that the peptidoglycan, the exoskeleton of the bacterial cell, of M. abscessus is unique in the final step of its synthesis compared to other gram negative and gram positive bacteria. Furthermore, this distinction is due to the activities of non-classical transpeptidases. I will study the relevance of these novel transpeptidases to the physiology of M. abscessus peptidoglycan and their contribution during acute and chronic stages of pulmonary infection. Investigating M. abscessus in vivo is critical, however current published accounts of mouse models often lack a sustained chronic infection analogous to what would occur in cystic fibrosis or bronchiectasis patients. They also lack demonstrated progression to pathology. I have developed a mouse model which fulfills both of these criteria, generating not only a chronic M. abscessus pulmonary infection, but also leading to gross pathological findings that mimic those observed in humans. The studies outlined in this proposal will provide new insights into aspects of M. abscessus cell wall metabolism and physiology during infection that could lead to novel therapeutic development and novel chemotherapy regimens of existing antibiotics.

项目总结 有结构性肺部疾病的患者，如囊性纤维化和支气管扩张，极易患上 感染脓肿分枝杆菌。这些病原体在约13%的囊性纤维化患者的痰中检测到 在美国的病人。除了有潜在肺部疾病的人外，绝经后具有免疫能力的人 高加索女性也选择性地易患肺部脓肿分枝杆菌感染。尽管不断增加 虽然这种疾病的发病率很高，但对脓肿支原体肺部感染的发病机制知之甚少。 这项建议的目的是填补我们对肺部脓肿分支杆菌感染的理解的关键空白。近期 研究表明，脓肿分枝杆菌细菌细胞的外骨骼--肽聚糖是 与其他革兰氏阴性和革兰氏阳性细菌相比，它在合成的最后一步中具有独特性。此外， 这种区别是由于非经典转肽酶的活性所致。我会研究这些小说的相关性 转肽酶对脓肿支原体肽聚糖生理的影响及其在急、慢性过程中的作用 肺部感染的分期。在活体内研究脓肿分枝杆菌是至关重要的，然而目前已发表的报道 的小鼠模型通常缺乏持续的慢性感染，类似于囊性纤维化或 支气管扩张症患者。它们也缺乏向病理学发展的证据。我开发了一个小鼠模型 符合这两个标准，不仅产生慢性脓肿支原体肺部感染，而且 导致了与在人类身上观察到的结果相似的大体病理发现。 这项提案中概述的研究将为脓肿分支杆菌细胞壁新陈代谢提供新的见解。 和感染期间的生理学，可能导致新的治疗开发和新的化疗 现有抗生素的治疗方案。