Understanding in vivo antibiotic resistance in diverse Pseudomonas aeruginosa populations

摘要 囊性纤维化是一种遗传性疾病，可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。机会细菌铜绿假单胞菌 在患者年轻时感染肺部并持续一生的病原体是一种主要的 促成因素。积极的抗生素制度显著延长了CF的生命 然而，在终末期肺部疾病中，PA人群仍然占主导地位。为什么选择抗生素 针对帕金森氏症的治疗最终失败仍不清楚，但一个可信的解释是，帕金森氏症 CF肺中的种群在变得更多时，集体获得更高的AMR水平 随着时间的推移，表型和基因的多样性。了解PA种群异质性 导致抗菌素耐药性(AMR)，以及PA种群多样性如何有助于 生物体的生存，是未来有效发展的重要考虑因素 诊断和治疗策略。对体内AMR的理解由于缺乏经验而受到限制 研究集中在进化权衡和社会互动等因素是如何 PA分离株影响异质性并影响AMR。这项研究将重点放在内部的影响 利用已从50个国家收集的一组独特的PA菌株种群研究AMR的物种多样性 痰样本。主要目标是：(I)揭示PA种群的异质性水平如何 确定AMR的程度；(Ii)确定导致AMR的进化因素 异质性；(Iii)利用基因组广谱关联技术在体内鉴定AMR的基因组特征 研究(GWAS)。该项目中描述的研究将为 慢性CF感染的抗菌素耐药性，因为它将为 考虑人口动态的临床药敏试验。结果 也可能为研究毒力和AMR的进化提供新的模型和平台 人口。在未来，这里提出的想法可以进一步扩展到包括研究 在CF和其他多微生物群落中重要的其他物种上。

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.