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.

项目摘要 改善感染结果的进展取决于理解减少抗生素作用的因素。 最近的工作表明抗生素异质抗性可能是一个关键因素。杂质病原体展示 人口级抗性异质性，这意味着它们包含高度抵抗的亚群，并且通常 表现出不稳定的耐药性，这意味着在没有抗生素的情况下生长时有些细胞会迅速敏感。 该提案侧重于这两种表型，因为它们被认为对易感性有重大影响 测试和抗生素功效。在这里，我们建议研究人口级抵抗的异质性和 囊性纤维化（CF）和慢性假单胞菌（PA）的人的不稳定性 循环和关闭吸入毒素的感染。 CF为这些研究提供了关键的优势，因为它是一种单基因疾病，具有均匀的表现， 单个细菌物种对同一抗生素的反应可以在相当大的同类中进行研究，并且可以研究 存在基础设施是为了在抗生素“ ON”和 “关”期。这些优势以及我们的初步工作中开发的方法使我们能够测试 来自慢性感染患者的PA的假设表现出明显的种群抗性异质性 和不稳定的抵抗；该因素的参数预测了对治疗的临床反应； CF PA中的不稳定抗性是由于一组核心基因扩增和能力补偿 点突变。这项工作将产生有关抗生素杂质的基础知识，可以 提高对CF中抗生素治疗失败的了解，并提出新的精密医学方法 选择抗生素并改善结果。这些发现还可以指导未来的感染中的工作 异质性，病原体和治疗多样性以及较少发达的基础设施使研究更加困难。