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: 10318912
• 负责人: Brian Patrick Conlon
• 金额: $ 38.47万
• 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/10318912
• 关键词: Adjuvant; Alginates; Aminoglycoside resistance; Aminoglycosides; Anaerobic Bacteria; Antibiotic Resistance; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Bacteria; Bacterial Infections; Biological Assay; Catheters; Cell Membrane Permeability; Cell Wall; Chemosensitization; Ciprofloxacin; Clinic; Clinical; Complex; 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 Cystic 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; burn model; burn wound; 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 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，过度依赖于涉及纯细菌培养物和受控细菌培养物的敏感性测定。 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，这些测定不能解释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 导致许多难以治疗的感染和抗生素治疗失败是常见的。的 识别新的外在因素，显着影响S。体内金黄色葡萄球菌抗生素敏感性将 大大提高了我们预测患者抗生素疗效的能力，从而改善了治疗效果。 这些因素可能包括宿主相互作用、营养和氧气的可用性以及与其他环境的相互作用。 微生物在多微生物感染期间。 我们的初步研究表明，铜绿假单胞菌产生的分子显着改变S。 金黄色葡萄球菌抗生素敏感性我们发现，这些分子的生产是高度可变的P。 铜绿假单胞菌临床分离株在小鼠身上进行的初步实验表明，这些相互作用在 在体内测定抗生素的功效。 我们假设铜绿假单胞菌强烈影响S。患者对金黄色葡萄球菌抗生素的敏感性 在多微生物感染期间。 在目标1中，我们建议阐明这种改变抗生素疗效的分子机制。 阐明这些机制将有助于我们对S.金黄色葡萄球菌抗生素耐受性，也可能 导致开发用于根除S.金黄色葡萄球菌种群。 目的2：确定铜绿假单胞菌/S.金黄色葡萄球菌相互作用的患者，我们将 检查来自烧伤和囊性纤维化患者的临床分离物对。 在目标3中，为了确定感染期间这些相互作用的相关性，我们将研究抗生素 对S.金黄色葡萄球菌单一感染和在与铜绿假单胞菌共感染期间使用两个互补的 感染的小鼠模型。 总之，这些实验有望揭示细菌相互作用在决定细胞增殖中的作用。 抗生素治疗S.金黄色。这将有助于未来开发更先进， 更准确的易感性测定和改善患者的治疗结果。

项目成果

Antibiotic-induced accumulation of lipid II synergizes with antimicrobial fatty acids to eradicate bacterial populations.

• DOI: 10.7554/elife.80246
• 发表时间: 2023-03-06
• 期刊: eLife
• 影响因子: 7.7
• 作者: Sidders AE;Kedziora KM;Arts M;Daniel JM;de Benedetti S;Beam JE;Bui DT;Parsons JB;Schneider T;Rowe SE;Conlon BP
• 通讯作者: Conlon BP

Harnessing ultrasound-stimulated phase change contrast agents to improve antibiotic efficacy against methicillin-resistant Staphylococcus aureus biofilms.

利用超声刺激的相位变化对比剂，以提高针对耐甲氧西林的金黄色葡萄球菌生物膜的抗生素疗效。

• DOI: 10.1016/j.bioflm.2021.100049
• 发表时间: 2021-12
• 期刊: Biofilm
• 影响因子: 6.8
• 作者: Durham PG;Sidders AE;Beam JE;Kedziora KM;Dayton PA;Conlon BP;Papadopoulou V;Rowe SE
• 通讯作者: Rowe SE

Antibiotic Tolerance and Treatment Outcomes in Cystic Fibrosis Methicillin-Resistant Staphylococcus aureus Infections.

• DOI: 10.1128/spectrum.04061-22
• 发表时间: 2023-02-14
• 期刊: Microbiology spectrum
• 影响因子: 3.7

Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia: Host, Pathogen, and Treatment.

• DOI: 10.3390/antibiotics12030455
• 发表时间: 2023-02-24
• 期刊: ANTIBIOTICS-BASEL
• 影响因子: 4.8
• 作者: Parsons, Joshua. B.;Westgeest, Annette. C.;Conlon, Brian. P. B.;Fowler, Vance. G., Jr.
• 通讯作者: Fowler, Vance. G., Jr.