Antibiotic-mediated Adaptation of Pseudomonas aeruginosa

抗生素介导的铜绿假单胞菌适应

• 批准号: 6962112
• 负责人: Lucas R Hoffman
• 金额: $ 12.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6962112
• 关键词: Pseudomonas aeruginosa; adolescence (12-20); aminoglycoside antibiotics; biofilm; biological signal transduction; biomarker; cell surface receptors; child (0-11); clinical research; cystic fibrosis; densitometry; drug resistance; genetic strain; guanosine monophosphate; host organism interaction; human subject; longitudinal human study; membrane proteins; microorganism growth; opportunistic infections; quorum sensing; respiratory infections; thin layer chromatography; virulence

DESCRIPTION (provided by applicant): This application describes a 5-year plan to establish an independent career in academic pediatric pulmonology. The candidate's long-term goal is to develop an interdisciplinary research program focusing on microbial pathogenesis in lung infections while maintaining a clinical practice encompassing 20% of the candidate's time. The training environment consists of the laboratory of Dr. Samuel Miller at the University of Washington and the Pulmonary Division at Children's Hospital & Regional Medical Center, both in Seattle. The candidate will expand his research expertise through a project with basic and translational components, augmented by collaboration and advising from senior scientists and clinicians. The formation of bacterial biofilms is associated with antibiotic resistance. One of the best-studied model systems is the chronic Pseudomonas aeruginosa airway infection in people with cystic fibrosis (CF). P. aeruginosa infects CF airways as a biofilm, and it adapts to the CF airway environment during infection. These adaptations affect bacterial responses to antibiotics. Preliminary data demonstrate that P. aeruginosa responds specifically to subinhibitory concentrations of the antibiotic tobramycin with increased biofilm formation. Tobramycin-induced biofilms are more resistant to further antibiotic challenge. Preliminary evidence suggests a role for two cell signaling systems, quorum sensing and the cyclic diguanylate pathway, in the response to tobramycin. Published data led to the hypothesis that responses to tobramycin vary among CF P. aeruginosa isolates, with variable effects on progression of lung disease. We propose to determine the molecular mechanism of the biofilm response of a laboratory strain of P. aeruginosa to tobramycin using available resources (Specific Aim 1). The clinical relevance of this response will then be determined by examining archived clinical isolates from CF patients, as well as environmental strains of P. aeruginosa (Specific Aim 2). The ultimate goal of this project is to identify novel therapeutic targets to inhibit the development of antibiotic resistance, and to aid eradication of chronic infections. The techniques and environments in this proposal are ideal for preparing for a career in the study of lung infections in children.

描述（由申请人提供）：本申请描述了在儿科肺病学学术领域建立独立职业生涯的 5 年计划。候选人的长期目标是开发一个跨学科研究项目，重点关注肺部感染的微生物发病机制，同时维持占候选人 20% 时间的临床实践。培训环境包括华盛顿大学 Samuel Miller 博士的实验室以及西雅图儿童医院和地区医疗中心的肺科。候选人将通过一个包含基础和转化部分的项目来扩展他的研究专业知识，并通过资深科学家和临床医生的合作和建议来增强。 细菌生物膜的形成与抗生素耐药性有关。研究最好的模型系统之一是囊性纤维化 (CF) 患者的慢性铜绿假单胞菌气道感染。铜绿假单胞菌作为生物膜感染CF气道，并在感染过程中适应CF气道环境。这些适应影响细菌对抗生素的反应。初步数据表明，铜绿假单胞菌对抗生素妥布霉素的亚抑制浓度有特异性反应，并增加生物膜形成。妥布霉素诱导的生物膜对进一步的抗生素挑战更具抵抗力。初步证据表明，群体感应和环二鸟苷酸途径这两个细胞信号系统在妥布霉素的反应中发挥着作用。已发表的数据得出这样的假设：CF 铜绿假单胞菌分离株对妥布霉素的反应各不相同，对肺部疾病进展的影响也不同。我们建议利用现有资源确定铜绿假单胞菌实验室菌株对妥布霉素的生物膜反应的分子机制（具体目标 1）。然后，将通过检查 CF 患者的存档临床分离株以及铜绿假单胞菌的环境菌株来确定该反应的临床相关性（具体目标 2）。该项目的最终目标是确定新的治疗靶点，以抑制抗生素耐药性的发展，并帮助根除慢性感染。该提案中的技术和环境非常适合为儿童肺部感染研究的职业做好准备。