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Impact of Fluoroquinolone resistance on Pseudomonas virulence and patient outcome

氟喹诺酮类药物耐药性对假单胞菌毒力和患者预后的影响

基本信息

批准号：
7688035
负责人：
Annie Wong-Beringer
金额：
$ 20.35万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-16 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7688035
关键词：
Acute Acute Pneumonia Adult Advanced Development Americas Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antibodies Bacteremia Bacteria Behavior Therapy Biological Assay Cell Death Cell model Cells Cessation of life Classification Clinical Clinical Research Communicable Diseases Country Cytotoxin DNA Gyrase DNA Topoisomerase IV Data Development Diagnostic Disease Drug Delivery Systems Drug Industry Drug Prospecting Drug resistance Enzyme-Linked Immunosorbent Assay Enzymes Epithelial Epithelial Cells European Exposure to Fluoroquinolones Genes Genetic Transcription Goals Human Immunotherapy In Vitro Infection Infection Control Intensive Care Units Intervention Length of Stay Levaquin Light Link Lung Measures Metabolic Microbe Molecular Molecular Models Morbidity - disease rate Multi-Drug Resistance Mutation Nosocomial Infections Nursing Homes Outcome Pathway interactions Patient Care Patients Pneumonia Population Predisposition Production Proteins Pseudomonas Pseudomonas aeruginosa Public Health Resistance Reverse Transcriptase Polymerase Chain Reaction Role Sampling Societies Superhelical DNA Surveys Testing Therapeutic Time Toxic effect Toxin Translating Type III Secretion System Pathway Urinary tract infection Vaccines Ventilator Virulence Virulence Factors Virulent bacterial resistance base clinical research site cytotoxicity design efflux pump fluoroquinolone resistance mRNA Expression molecular modeling mortality novel novel therapeutics overexpression pathogen public health relevance resistance mutation resistant strain respiratory response

项目摘要

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa (PA) is a bacterium that poses an immediate threat to public health because of its leading role in causing nosocomial infections, emergence of multidrug-resistance, virulence potential, and the lack of new drugs targeting this pathogen in the development pipeline. During acute infections, PA utilizes the type III secretion system (TTSS) to deliver cytotoxins (i.e. ExoU, ExoS) into host cells upon contact, ultimately allowing PA to cross epithelial barrier and spread systemically or cause cell death. Most PA isolates contain either exoS or exoU gene; its presence varies by clinical sites or disease backgrounds. Excess morbidity and mortality have been demonstrated for acute pneumonia caused by ExoU-secreting PA and FQ-resistant PA, raising the possibility that antibiotic resistance may be linked with enhanced virulence. Preliminary data indicates that FQ-resistant PA population is predominated by exoU+ strains, with increased cytotoxicity towards cultured epithelial cells for those showing higher degree of resistance. We hypothesize that exoU+ PA strains adapt more readily to FQ exposure by developing mutations at target enzymes (e.g. DNA gyrase) which simultaneously confer resistance to FQ and upregulate TTSS gene transcription due to changes in DNA supercoiling. We are first to propose a systematic approach to determine if FQ-resistant PA strains are more virulent as a necessary initial step towards the development of novel management strategies urgently needed for infections caused by multi-drug resistant PA. We will examine a large sample of respiratory isolates (n=216) obtained from patients with PA pneumonia and available outcome data already collected to: 1) determine if FQ resistance is more frequently observed in exoU+ compared to exoS+ strains, 2) assess the extent to which co-expression of resistance and virulence in clinical isolates translates into a biologic effect in in vitro cellular model and correlates with outcomes of patients, and 3) study the dynamics of virulence expression as resistance mutations accumulate in PA strains following repeated exposure to FQ. If we prove that PA evolves into a "superbug" in response to FQ exposure by becoming more resistant and more virulent, we will have a strong basis to 1) prescribe more aggressive treatment with early and more intensive therapy, 2) severely limit indiscriminant prescribing of the FQs and at the same time, intensify current infection control efforts to minimize spread of FQ-resistant and virulent strains. We will have a strong basis to screen existing compounds that can block TTSS virulence as well as identify novel drug targets based on a better understanding of the molecular pathways that regulate resistance and virulence expression. Our hypothesis if proven will help advance the development of immunotherapy against the type III effectors (pcrV vaccine, anti-PcrV antibody) and also rapid diagnostics to determine virulence potential as an essential part of patient care. PUBLIC HEALTH RELEVANCE: The goal of this project is to confirm if Pseudomonas aeruginosa, a leading cause of nosocomial infections, becomes more virulent as it becomes resistant to the fluoroquinolone antibiotics and prove the molecular model by which this co-expression occurs. The lack of new drugs targeting this pathogen in the development pipeline underscores the urgent need to perform this study as a necessary initial step in order to gain a better understanding of the operative virulence strategies in the resistant strains so that novel therapeutics aim at disarming virulence can be developed.

描述（由申请方提供）：铜绿假单胞菌（PA）是一种对公共卫生构成直接威胁的细菌，因为其在引起医院感染、出现多重耐药性、毒力潜力方面起主导作用，并且在开发管道中缺乏靶向该病原体的新药。在急性感染期间，PA利用III型分泌系统（TTSS）在接触时将细胞毒素（即ExoU、ExoS）递送到宿主细胞中，最终允许PA穿过上皮屏障并全身扩散或导致细胞死亡。大多数PA分离株含有exoS或exoU基因;其存在因临床部位或疾病背景而异。已经证明了由分泌ExoU的PA和耐药PA引起的急性肺炎的发病率和死亡率过高，这增加了抗生素耐药性可能与增强的毒力有关的可能性。初步数据表明，抗Escherichia coli的PA群体主要由exoU+菌株，对于那些显示出较高程度的抗性的细胞，对培养的上皮细胞的细胞毒性增加。我们假设exoU + PA菌株通过在靶酶（例如DNA促旋酶）处发生突变而更容易适应FQ暴露，所述靶酶同时赋予对FQ的抗性并由于DNA超螺旋的变化而上调TTSS基因转录。我们首先提出了一个系统的方法来确定是否耐药PA菌株更毒力作为一个必要的第一步，对开发新的管理策略，迫切需要由多药耐药PA引起的感染。我们将检查从PA肺炎患者中获得的大量呼吸道分离株样本（n = 216）和已收集的可用结局数据，以：1）确定与exoS+菌株相比，在exoU+中是否更频繁地观察到FQ抗性，（2）在多大程度上，临床分离株中耐药性和毒力的表达在体外细胞模型中转化为生物学效应，并与患者，和3）研究毒力表达的动力学作为耐药突变的积累PA菌株反复暴露于FQ。如果我们证明PA通过变得更耐药和更具毒性而演变成响应于FQ暴露的"超级细菌"，我们将有一个强有力的基础1）通过早期和更强化的治疗开出更积极的治疗，2）严格限制不加区别地开出FQ，同时，加强当前的感染控制工作，以最大限度地减少耐药和毒性菌株的传播。我们将有一个强大的基础来筛选现有的化合物，可以阻止TTSS毒力，以及确定新的药物靶点的基础上更好地了解调节耐药性和毒力表达的分子途径。我们的假设如果得到证实，将有助于促进针对III型效应物（pcrV疫苗，抗PcrV抗体）的免疫疗法的发展，以及快速诊断以确定毒力潜力作为患者护理的重要组成部分。公共卫生关系：该项目的目标是确认铜绿假单胞菌（院内感染的主要原因）是否在对氟喹诺酮类抗生素产生耐药性时变得更具毒性，并证明这种共表达发生的分子模型。在开发管道中缺乏针对这种病原体的新药强调了迫切需要进行这项研究作为必要的初始步骤，以便更好地了解耐药菌株中的有效毒力策略，以便开发旨在解除毒力的新疗法。