Understanding in vivo antibiotic resistance in diverse Pseudomonas aeruginosa populations

了解不同铜绿假单胞菌群体的体内抗生素耐药性

• 批准号: 10390346
• 负责人: Stephen Paul Diggle
• 金额: $ 48.06万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-09 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390346
• 关键词: Acute; Affect; Age; Antibiotic Resistance; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Antimicrobial Resistance; Antimicrobial susceptibility; Area; Bacteria; Bacterial Genome; Biological Assay; Chronic; Clinic; Clinical; Communicable Diseases; Communities; Confocal Microscopy; Correlation Studies; Cystic Fibrosis; Development; Diagnostic tests; Evolution; Future; Genes; Genetic; Genetic Diseases; Genetic Heterogeneity; Genetic Recombination; Goals; Growth; Heterogeneity; Individual; Lead; Life; Link; Lung; Lung diseases; Lung infections; Methodology; Microbial Biofilms; Modeling; Mucins; Mutation; Organism; Outcome; Patients; Phenotype; Phylogeny; Physiology; Population; Population Dynamics; Population Heterogeneity; Privatization; Problem Solving; Production; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pulmonary Cystic Fibrosis; Regulatory Pathway; Research; Resistance; Sampling; Social Interaction; Source; Sputum; Structure; Testing; Time; Variant; Virulence; Virulence Factors; Work; base; beta-Lactamase; computational platform; cystic fibrosis infection; cystic fibrosis patients; de novo mutation; diagnostic strategy; emerging antimicrobial resistance; experience; experimental study; fitness; follow-up; genome analysis; genome wide association study; genomic biomarker; genomic locus; genomic signature; homologous recombination; in vivo; insight; mRNA Differential Displays; novel; novel diagnostics; opportunistic pathogen; pathogenic bacteria; predict clinical outcome; pulmonary function; reconstruction; resistance mechanism; resistant strain; social; trait; transcriptome sequencing; treatment strategy

Summary Cystic fibrosis (CF) is a genetic disease that results in persistent and chronic lung infections which reduce lung function over time. Pseudomonas aeruginosa (Pa), an opportunistic bacterial pathogen that infects patients lungs at a young age and persists throughout life, is a major contributing factor. Aggressive antibiotic regimes have significantly prolonged the lives of CF patients, yet Pa populations still dominate during end stage lung disease. Why antibiotic treatments against Pa ultimately fail remains unclear, but one plausible explanation is that Pa populations in the CF lung gain higher levels of AMR collectively as they become more phenotypically and genetically diverse over time. Understanding how Pa population heterogeneity contributes to antimicrobial resistance (AMR), and how Pa population diversity contributes to the organism’s survival, are important considerations for the future development of effective diagnostic and treatment strategies. Understanding of in vivo AMR is limited by a lack of empirical studies focused on how factors such as evolutionary trade-offs and social interactions between Pa isolates affect heterogeneity and influence AMR. This study will focus on the impact of intra- species diversity on AMR using a unique set of Pa strain populations already collected from 50 sputum samples. The main goals are to (i) reveal how the level of heterogeneity in Pa populations in CF patients determines the extent of AMR; (ii) ascertain evolutionary factors that leads to AMR heterogeneity; (iii) identify in vivo genomic signatures of AMR using Genome Wide Association Studies (GWAS). The research described in this project will provide valuable insights into antimicrobial resistance in chronic CF infection, because it will introduce novel methodology for antimicrobial susceptibility testing in clinics by taking population dynamics into account. Outcomes could also lead to new models and platforms for studying the evolution of virulence and AMR in populations. In the future, the ideas presented here can be further expanded to include studies on other species important in CF and other polymicrobial communities.

概括 囊性纤维化（CF）是一种遗传性疾病，会导致持续性和慢性肺部感染， 随着时间的推移，肺功能会降低。铜绿假单胞菌 (Pa)，一种机会性细菌 在患者年轻时感染肺部并持续终生的病原体是主要的 促成因素。积极的抗生素治疗显着延长了CF的寿命 患者，但 Pa 人群在终末期肺病期间仍然占主导地位。为什么选择抗生素 针对 Pa 的治疗最终失败仍不清楚，但一个合理的解释是 Pa 随着 CF 肺中的人群变得越来越多，他们的 AMR 水平集体提高。 随着时间的推移，表型和遗传发生多样性。了解 Pa 群体异质性如何 导致抗菌素耐药性 (AMR)，以及 Pa 种群多样性如何促进抗菌素耐药性 (AMR) 有机体的生存，是未来有效发展的重要考虑因素 诊断和治疗策略。由于缺乏实证研究，对体内 AMR 的理解受到限制 研究重点是进化权衡和社会互动等因素如何影响 Pa 分离株影响异质性并影响 AMR。本研究将重点关注内部的影响 使用已从 50 个国家收集的一组独特的 Pa 菌株种群来评估 AMR 的物种多样性 痰样本。主要目标是 (i) 揭示 Pa 群体的异质性水平如何 CF 患者的 AMR 程度决定； (ii) 确定导致 AMR 的进化因素 异质性； (iii) 使用全基因组关联鉴定 AMR 的体内基因组特征 研究（GWAS）。该项目中描述的研究将为以下方面提供宝贵的见解： 慢性 CF 感染的抗菌药物耐药性，因为它将引入新的方法 考虑人口动态，在诊所进行抗菌药物敏感性测试。结果 还可能带来用于研究毒力和抗菌素耐药性进化的新模型和平台 人口。将来，这里提出的想法可以进一步扩展到包括研究 对 CF 和其他多微生物群落中重要的其他物种的影响。