Antibiotic activities against S. aureus during P. aeruginosa co-infection

铜绿假单胞菌合并感染期间针对金黄色葡萄球菌的抗生素活性

基本信息

批准号：
9917929
负责人：
Brian Patrick Conlon
金额：
$ 4.64万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917929
关键词：
Adjuvant Alginates Aminoglycoside resistance Aminoglycosides Anaerobic Bacteria Antibiotic Resistance Antibiotic Therapy Antibiotic susceptibility Antibiotics Bacteria Bacterial Infections Biological Assay Burn injury Catheters Cell Membrane Permeability Cell Wall Chemosensitization Ciprofloxacin Cleaved cell Clinic Clinical Complex Cystic Fibrosis Data Development Drops Environment Enzymes Exhibits Failure Fluoroquinolones Future Genotype Glycopeptides Growth Immunologic Factors Implant Infection Lead Length of Stay Measurement Measures Mediating Microbial Biofilms Modeling Molecular Mus Nutrient Outcome Oxacillin Oxides Oxygen Patients Penetration Peptidoglycan Physiological Play Population Predisposition Production Proton-Motive Force Pseudomonas aeruginosa Pulmonary Fibrosis Quantitative Reverse Transcriptase PCR Regulation Reporter Respiration Role Staphylococcus aureus Testing Tobramycin Treatment Failure Treatment outcome Vancomycin Western Blotting Work antibiotic tolerance bactericide beta-Lactams clinically relevant clinically significant co-infection cystic fibrosis patients experience experimental study improved in vivo microorganism mortality mouse model mutant novel quorum sensing rhamnolipid success surfactant uptake

项目摘要

Summary Abstract Predicting the efficacy of an antibiotic in a patient is a critical component of successfully treating infection. Currently, there is an over-reliance on susceptibility assays involving pure bacterial cultures and controlled growth conditions. These conditions are drastically different to those experienced by the bacteria during infection. Hence, these assays fail to account for extrinsic factors that influence antibiotic susceptibility in the infection environment. This contributes to unacceptable rates of treatment failure. Staphylococcus aureus is responsible for numerous difficult-to-treat infections and antibiotic treatment failure is common. The identification of novel extrinsic factors that significantly influence S. aureus antibiotic susceptibility in vivo will greatly improve our ability to predict antibiotic efficacy in patients, leading to improved treatment outcomes. These factors may include host interactions, nutrient and oxygen availability and interactions with other microorganisms during polymicrobial infection. Our preliminary studies demonstrate that P. aeruginosa produced molecules dramatically alter S. aureus antibiotic susceptibility. We find the production of these molecules is highly variable among P. aeruginosa clinical isolates. Preliminary experiments in mice suggest these interactions play an important role in determining antibiotic efficacy in vivo. We hypothesize that P. aeruginosa strongly influences S. aureus antibiotic susceptibility in patients during polymicrobial infection. In Aim 1, we propose to elucidate the molecular mechanisms responsible for this altered antibiotic efficacy. Elucidation of these mechanisms will improve our understanding of S. aureus antibiotic tolerance and may also lead to the development of novel adjuvants for the eradication of S. aureus populations. In Aim 2, to determine the importance of P. aeruginosa/S. aureus interactions in patients, we will examine clinical isolate pairs from burn and cystic fibrosis patients. In Aim 3, to determine the relevance of these interactions during infection, we will examine antibiotic efficacy against S. aureus mono-infection and during co-infection with P. aeruginosa using two complimentary mouse models of infection. Together, these experiments promise to reveal the role of bacterial interaction in determining the outcome of antibiotic treatment of S. aureus. This will facilitate the future development of more sophisticated, more accurate susceptibility determination and improved treatment outcomes in patients.

摘要摘要预测抗生素对患者的疗效是成功治疗感染的关键组成部分。目前，过度依赖涉及纯细菌培养物和受控细菌的药敏试验。生长条件。这些条件与细菌在生长过程中所经历的条件截然不同。感染。因此，这些测定未能考虑影响抗生素敏感性的外在因素。感染环境。这导致了不可接受的治疗失败率。金黄色葡萄球菌是造成许多难以治疗的感染并且抗生素治疗失败的情况很常见。这鉴定显着影响金黄色葡萄球菌体内抗生素敏感性的新外在因素将大大提高了我们预测患者抗生素疗效的能力，从而改善治疗结果。这些因素可能包括宿主相互作用、营养物和氧气的可用性以及与其他物质的相互作用。多种微生物感染期间的微生物。我们的初步研究表明，铜绿假单胞菌产生的分子极大地改变了铜绿假单胞菌。金黄色葡萄球菌抗生素敏感性。我们发现这些分子的产生在 P. 铜绿假单胞菌临床分离株。小鼠的初步实验表明这些相互作用发挥着重要作用确定抗生素体内功效。我们假设铜绿假单胞菌强烈影响患者对金黄色葡萄球菌的抗生素敏感性在多种微生物感染期间。在目标 1 中，我们建议阐明导致抗生素功效改变的分子机制。阐明这些机制将提高我们对金黄色葡萄球菌抗生素耐受性的理解，也可能导致开发出用于根除金黄色葡萄球菌种群的新型佐剂。在目标 2 中，确定铜绿假单胞菌/S 的重要性。金黄色葡萄球菌在患者中的相互作用，我们将检查烧伤和囊性纤维化患者的临床分离对。在目标 3 中，为了确定感染期间这些相互作用的相关性，我们将检查抗生素使用两种互补方法对金黄色葡萄球菌单一感染和铜绿假单胞菌共同感染期间的功效小鼠感染模型。总之，这些实验有望揭示细菌相互作用在确定金黄色葡萄球菌抗生素治疗的结果。这将有利于未来更加复杂、更准确的药敏测定并改善患者的治疗结果。