Prevalence, Consequences and Mechanisms of Antibiotic Heteroresistance in Cystic Fibrosis

囊性纤维化抗生素异抗性的患病率、后果和机制

• 批准号: 10686807
• 负责人: PRADEEP k SINGH
• 金额: $ 59.07万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686807
• 关键词: Accounting; Affect; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Cells; Chronic; Clinical; Clinical Research; Compensation; Cystic Fibrosis; Cystic Fibrosis sputum; Data; Disease; Exhibits; Future; Gene Amplification; Generations; Genetic; Growth; Heterogeneity; Individual; Infection; Infrastructure; Inhalation; Intermediate resistance; Knowledge; Link; Measurement; Measures; Mendelian disorder; Methods; Mutation; Organism; Outcome; Patients; Persons; Phenotype; Point Mutation; Population; Population Study; Predictive Factor; Predisposition; Prevalence; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Research Infrastructure; Resistance; Respiratory Signs and Symptoms; Site; Specimen; Sputum; Testing; Time; Tobramycin; Treatment Failure; Treatment Protocols; Treatment outcome; Work; clinical effect; clinical predictors; cohort; cystic fibrosis patients; density; fitness; improved; improved outcome; in vivo; pathogen; personalized medicine; precision medicine; preservation; pulmonary function; response; treatment response

Project Summary Progress in improving infection outcomes depends upon understanding factors that diminish antibiotic action. Recent work suggests antibiotic heteroresistance may be a key factor. Heteroresistant pathogens exhibit population-level resistance heterogeneity, meaning they contain highly resistant subpopulations, and often exhibit unstable resistance, meaning some cells become rapidly sensitive when grown without antibiotics. This proposal focuses on these two phenotypes as they are postulated to have major effects on susceptibility testing and antibiotic efficacy. Here we propose to study population-level resistance heterogeneity and unstable resistance in people with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa (Pa) infections who cycle on and off inhaled tobramycin. CF offers key advantages for these studies as it is a monogenic disease with uniform manifestations, the responses of a single bacterial species to the same antibiotic can be studied in sizable cohorts, and infrastructure exists to procure primary specimens from the infected site (sputum) during antibiotic "on" and "off" periods. These advantages, and methods developed in our preliminary work enable us to test the hypotheses that Pa from chronically-infected patients exhibit marked population-level resistance heterogeneity and unstable resistance; that parameters accounting for these factors predict clinical responses to treatment; and that unstable resistance in CF Pa is due to a core set of gene amplifications and fitness-compensating point mutations. This work will generate foundational knowledge about antibiotic heteroresistance that could improve understanding of antibiotic treatment failure in CF, and suggest new precision medicine approaches to select antibiotics and improve outcomes. The findings could also guide future work in infections where patient heterogeneity, pathogen and treatment diversity, and less developed infrastructure make studies more difficult.

项目概要 改善感染结果的进展取决于对削弱抗生素作用的因素的了解。 最近的研究表明抗生素异质耐药性可能是一个关键因素。异抗性病原体表现出 群体水平的耐药异质性，意味着它们包含高度耐药的亚群，并且通常 表现出不稳定的耐药性，这意味着一些细胞在没有抗生素的情况下生长时会迅速变得敏感。 该提案重点关注这两种表型，因为假定它们对易感性有重大影响 测试和抗生素功效。在这里，我们建议研究人群水平的耐药异质性和 囊性纤维化 (CF) 和慢性铜绿假单胞菌 (Pa) 患者的抵抗力不稳定 循环断断续续吸入妥布霉素的感染者。 CF 为这些研究提供了关键优势，因为它是一种具有统一表现的单基因疾病， 可以在相当大的群体中研究单一细菌物种对相同抗生素的反应，并且 存在基础设施，可在抗生素“使用”期间从感染部位（痰）获取主要样本 “关闭”时期。这些优势以及我们在前期工作中开发的方法使我们能够测试 假设慢性感染患者的 Pa 表现出明显的群体水平耐药异质性 且电阻不稳定；考虑这些因素的参数可以预测治疗的临床反应； CF Pa 的不稳定抵抗力是由于一组核心基因扩增和适应性补偿造成的 点突变。这项工作将产生有关抗生素异质耐药性的基础知识，这些知识可以 提高对 CF 抗生素治疗失败的认识，并提出新的精准医学方法 选择抗生素并改善结果。这些发现还可以指导未来的感染工作 异质性、病原体和治疗方法的多样性以及欠发达的基础设施使研究变得更加困难。