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: 10590655
• 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/10590655
• 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; 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; 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; beta-Lactamase; computational platform; cystic fibrosis infection; cystic fibrosis patients; de novo mutation; diagnostic strategy; experience; experimental study; fitness; follow-up; genome analysis; genome wide association study; genomic biomarker; genomic locus; genomic signature; homologous recombination; improved; 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.

总结 囊性纤维化（CF）是一种遗传性疾病，导致持续性和慢性肺部感染， 随着时间的推移会降低肺功能。铜绿假单胞菌（Pa），一种机会细菌 在年轻时感染患者肺部并持续终生的病原体是一种主要的 促成因素。积极的抗生素方案显着延长了CF的寿命 患者，但Pa人群仍然占主导地位，在终末期肺病。为什么抗生素 对Pa的治疗最终失败仍不清楚，但一个合理的解释是Pa CF肺中的人群随着他们变得越来越多， 表型和遗传多样性随着时间的推移。了解Pa群体异质性 有助于抗菌素耐药性（AMR），以及Pa种群多样性如何有助于 生物体的生存，是未来发展的重要考虑因素， 诊断和治疗策略。对体内AMR的理解受到缺乏经验的限制。 研究的重点是如何因素，如进化的权衡和社会之间的相互作用， 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， 使用一组独特的Pa菌株种群对AMR的物种多样性进行了研究， 痰液样本主要目的是（i）揭示Pa种群的异质性水平 在CF患者中确定AMR的程度;（ii）确定导致AMR的进化因素 （iii）使用全基因组关联鉴定AMR的体内基因组特征 研究（GWAS）。本项目中描述的研究将为以下方面提供有价值的见解： 在慢性CF感染的抗菌药物耐药性，因为它将引入新的方法， 在临床上进行抗菌药物敏感性测试，考虑到人口动态。成果 也可能导致新的模型和平台，用于研究毒力和AMR的演变， 人口。在未来，这里提出的想法可以进一步扩大到包括研究 对CF和其他多微生物群落中的其他重要物种的影响。