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

• 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
• 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

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 预测抗生素在患者中的疗效是成功治疗感染的关键组成部分。 目前，过度依赖于纯细菌培养和对照的药敏试验。 生长条件。这些情况与细菌在过去几年经历的情况截然不同 感染。因此，这些分析没有考虑到影响患者抗生素敏感性的外部因素。 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 导致许多难以治疗的感染和抗生素治疗失败的情况很常见。这个 在体内发现显著影响金黄色葡萄球菌抗生素敏感性的新的外部因素将 极大地提高了我们预测患者抗生素疗效的能力，从而改善了治疗结果。 这些因素可能包括寄主之间的相互作用、养分和氧气的可用性以及与其他植物的相互作用 多菌物感染过程中的微生物。 我们的初步研究表明，铜绿假单胞菌产生的分子显著改变了S. 金黄色葡萄球菌对抗生素的敏感性。我们发现这些分子的产生在P. 铜绿假单胞菌临床分离株。在小鼠身上的初步实验表明，这些相互作用起着重要作用 在确定体内的抗生素疗效方面。 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疗效改变的分子机制。 阐明这些机制将提高我们对金黄色葡萄球菌耐药性的理解，还可能 导致开发用于根除金黄色葡萄球菌种群的新型佐剂。 在目标2中，为了确定铜绿假单胞菌/金黄色葡萄球菌相互作用在患者中的重要性，我们将 检查烧伤和囊性纤维化患者的临床分离株对。 在目标3中，为了确定感染过程中这些相互作用的相关性，我们将检查抗生素 抗金黄色葡萄球菌单一感染及与铜绿假单胞菌混合感染的疗效 感染的小鼠模型。 综上所述，这些实验有望揭示细菌相互作用在决定 金黄色葡萄球菌的抗生素治疗结果。这将有利于未来发展更复杂的、 更准确的敏感性测定和改善患者的治疗结果。