Impacts of host lipid composition on antimicrobial susceptibilities of Staphylococcus aureus

宿主脂质成分对金黄色葡萄球菌抗菌敏感性的影响

• 批准号: 10564729
• 负责人: Kelly M. Hines
• 金额: $ 41.87万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-14 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564729
• 关键词: Accounting; Affect; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic susceptibility; Antibiotics; Antimicrobial susceptibility; Bacteria; Cardiolipins; Cellular Morphology; Cessation of life; Charge; Clinical; Communities; Community-Acquired Infections; Complex; Daptomycin; Data; Endocarditis; Environment; Failure; Fatty Acids; Frequencies; Genus staphylococcus; Goals; Growth; Heart; Hospitals; Human; Human body; In Vitro; Infection; Infective endocarditis; Investigation; Isotope Labeling; Knowledge; Linoleic Acids; Lipids; Liquid Chromatography; Liquid substance; Mass Spectrum Analysis; Measurement; Membrane; Membrane Fluidity; Membrane Lipids; Methicillin; Methods; Microbial Biofilms; Monounsaturated Fatty Acids; Morphology; Multi-Drug Resistance; Nutrient; Oleic Acids; Organ; Outcome; Pathogenesis; Pathway interactions; Permeability; Phase; Phenotype; Phosphatidylglycerols; Phospholipids; Phosphotransferases; Physiological; Physiology; Polyunsaturated Fatty Acids; Predisposition; Prevalence; Prevention approach; Proteins; Reporting; Research; Resistance; Resolution; Role; Saturated Fatty Acids; Sepsis; Serum; Site; Skin; Soft Tissue Infections; Source; Stable Isotope Labeling; Staphylococcus aureus; Staphylococcus aureus infection; Structure; Supplementation; Surface; System; Systemic infection; Testing; Therapeutic; Time; Tissue Extracts; Tissues; Treatment Failure; Treatment Protocols; Unsaturated Fatty Acids; antibiotic tolerance; antimicrobial; antimicrobial tolerance; efflux pump; healthcare-associated infections; in vivo; lipid biosynthesis; lipidomics; liquid chromatography mass spectrometry; methicillin resistant Staphylococcus aureus; novel strategies; prevent; reversed phase chromatography; treatment risk

Although the CDC's 2019 report on Antibiotic Resistance Threats in U.S. shows that methicillin-resistant Staphylococcus aureus (MRSA) cases have declined, nearly 85% of all deaths attributed to antibiotic resistance between 2005 and 2016 were the result of MRSA infections. Bloodstream infections from community-acquired MRSA have declined less sharply than hospital-acquired MRSA during this time (-17% and -6.9%, respectively), whereas cases of community-associated methicillin-susceptible S. aureus (MSSA) have risen nearly 4%. Nearly half of all health-care-associated infections are now attributed to MSSA rather than MRSA. At the same time, MSSA and MRSA are being identified as the cause of infective endocarditis with greater frequency. The changing dynamics of S. aureus infections demonstrate the critical need to better our understanding of its pathogenesis in order to develop new approaches for prevention and treatment. One of the competitive advantages S. aureus has within the infection site is its ability to scavenge host-derived fatty acids to satisfy its own lipid biosynthesis needs. The mechanisms of the fatty acid kinase pathway are well-documented for monounsaturated fatty acids like oleic acid. However, the fatty acid content of the human body varies dramatically between different organs and tissues. Despite their prevalence in the human body, we have overlooked the role of host-derived saturated, straight-chain fatty acids (SCFAs) in investigations of the fatty acid kinase pathway. Our long-term goal is to increase the efficacy of existing antibacterial therapies by purposefully and selectively remodeling the staphylococcal membrane during infection. The overall objective for this application is to define the lipid composition of S. aureus within the complex environment of the mammalian host and identify the impacts of host-derived FAs on the antimicrobial susceptibilities of S. aureus. Our central hypothesis is that the S. aureus membrane mimics the fatty acyl composition of the infection site to a greater extent than previously thought and that the resulting impacts on membrane physiology modify the tolerance of S. aureus to antimicrobials. The rationale for this project is that more effective antimicrobial treatment regimens will be developed by accounting for or exploiting the lipid composition of S. aureus when residing within the mammalian host. In Aim 1, we will determine the prevalence and fate of mammalian-derived saturated and unsaturated fatty acids using advanced liquid chromatography-mass spectrometry-based lipidomics. In Aim 2, we will identify the impact of S. aureus' use of exogenous fatty acids on its membrane physiology and cell morphology. In Aim 3, we will test the hypothesis that host-derived fatty acids can influence antibiotic tolerances of S. aureus in vitro and in vivo. We expect that the results of our research will prompt greater appreciation and consideration of host-derived fatty acids as modulators of antibiotic susceptibility and tolerance, which will have the positive impact of reducing poor clinical outcomes from S. aureus infections.

尽管美国疾病预防控制中心（CDC）2019年有关抗生素抗性威胁的报告表明，耐甲氧西林 金黄色葡萄球菌（MRSA）案例已下降，几乎所有归因于抗生素耐药性的死亡中的85％ 在2005年至2016年之间，是MRSA感染的结果。社区获得的血液感染 在此期间 而与社区相关的甲氧西林敏感金黄色葡萄球菌（MSSA）的病例却增加了近4％。几乎 现在，与医疗保健相关的所有感染中有一半归因于MSSA，而不是MRSA。同时， MSSA和MRSA被确定为频率更高的感染性心内膜炎的原因。改变 金黄色葡萄球菌感染的动力学表明，至关重要的需要，以改善我们对其发病机理的理解 为了开发预防和治疗的新方法。竞争优势之一S.金黄色 在感染部位内有其清除宿主衍生的脂肪酸以满足其脂质生物合成的能力 需要。脂肪酸激酶途径的机制已充分证明了单不饱和脂肪酸 像油酸一样。但是，人体的脂肪酸含量在不同的器官之间差异很大 和组织。尽管它们在人体中的盛行，但我们还是忽略了宿主衍生的饱和， 在研究脂肪酸激酶途径中的直链脂肪酸（SCFA）。我们的长期目标是 通过有意，有选择地重塑，提高现有抗菌疗法的功效 感染过程中的葡萄球菌膜。该应用程序的总体目的是定义脂质 金黄色葡萄球菌在哺乳动物宿主的复杂环境中的组成，并确定 宿主源自金黄色葡萄球菌抗菌敏感性的FA。我们的中心假设是金黄色葡萄球菌 膜比以前想象的更大程度地模仿感染部位的脂肪酰基组成 对膜生理的影响会改变金黄色葡萄球菌对抗菌剂的耐受性。这 该项目的理由是，将通过会计制定更有效的抗菌治疗方案 用于或驻留在哺乳动物宿主中时，用于或利用金黄色葡萄球菌的脂质组成。在AIM 1中，我们将 使用先进的 液相色谱 - 质谱基脂肪组学。在AIM 2中，我们将确定金黄色葡萄球菌的影响 在其膜生理和细胞形态上使用外源脂肪酸。在AIM 3中，我们将测试 假设宿主衍生的脂肪酸可以在体外和体内影响金黄色葡萄球菌的抗生素耐受性。我们 预计我们的研究结果将促使人们对宿主衍生的脂肪的更加欣赏和考虑 酸作为抗生素易感性和耐受性的调节剂，这将产生降低较差的积极影响 金黄色葡萄球菌感染的临床结果。