The contribution of respiratory burst to antibiotic failure in Staphylococcus aureus bacteremia

呼吸爆发对金黄色葡萄球菌菌血症抗生素失效的影响

基本信息

批准号：
10666777
负责人：
Brian Patrick Conlon
金额：
$ 67.46万
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：
2022
资助国家：
美国
起止时间：
2022-08-22 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666777
关键词：
Acetylcysteine Address Antibiotic Resistance Antibiotic Therapy Antibiotic susceptibility Antibiotics Antioxidants Appearance Automobile Driving Bacteremia Blood Circulation CD59 Antigen Cells Clinical DNA DNA Damage Development Environment Evolution Failure Formulation Frequencies Human Immune response In Vitro Infection Measures Mediating Microbiology Modeling Monitor Mus Mutagenesis Mutant Strains Mice Nature Outcome Paper Patient-Focused Outcomes Patients Peripheral Blood Mononuclear Cell Persons Phagocytes Phagocytosis Phagolysosome Phenotype Plasma Population Positioning Attribute Predisposition Production RNA Reactive Oxygen Species Research Personnel Resistance Resistance development Resources Respiratory Burst Risk Role Scientist Sepsis Series Skin Tissue Soft Tissue Infections Staphylococcus aureus Staphylococcus aureus infection Study models Systemic infection Testing Therapeutic Treatment Failure Virulence Factors Vitamin B 12 antibiotic tolerance antimicrobial biobank chemotherapy human pathogen improved improved outcome in vivo macrophage monocyte mouse model multidisciplinary multidrug tolerance mutant nanoparticle novel novel therapeutic intervention pathogen prospective rosiglitazone targeted delivery therapeutic development tissue culture treatment risk

项目摘要

Summary Abstract Staphylococcus aureus infections are notoriously difficult to treat with antibiotics. Unlike many gram- negative pathogens where the risk of treatment failure is associated with the increasing spread of antibiotic resistance and the appearance of pan-resistant isolates, S. aureus remains largely susceptible to multiple antibiotics. However, despite apparent susceptibility, these antibiotic treatments frequently fail, and 20,000 people died from S. aureus infections in the U.S in 2017. S. aureus are well-equipped to survive phagocytosis and the phagolysosome of macrophages is increasingly appreciated as a major reservoir of S. aureus cells during infection. We find that, in a murine model of systemic infection, S. aureus not only survives within macrophages but also enters into a multidrug tolerant, persister state within this niche, rendering it untreatable with antibiotics. Our overall hypothesis is that macrophage-S. aureus interactions are driving antibiotic treatment failure in patients. To test this, in Aim 1, we will examine host macrophage induced antibiotic tolerance using clinical S. aureus isolates and patient matched macrophages, cultured from peripheral blood mononuclear cells taken from patients by Dr. Vance Fowler’s S. aureus bacteremia group (SABG). We will also examine if antibiotic tolerance induction by macrophages in tissue culture can predict patient outcomes. In Aim 2, we will examine if respiratory burst is also capable of generating antibiotic resistant cells in tissue culture and in a murine bacteremia model. The dual capacity of ROS produced by respiratory burst to induce antibiotic tolerance and mutagenesis creates an ideal environment for the evolution of antibiotic resistance during infection. In Aim 3, we will examine the potential of 2 therapeutic approaches to reduce antibiotic tolerance induction by macrophages. Firstly, we will apply a series of antioxidants, including a state-of the art approach involving the targeted delivery of therapeutics specifically to macrophages. Secondly, we will induce M2 polarization of macrophages to reduce ROS production and improve antibiotic susceptibility of phagocytosed S. aureus. In all, our proposal promises to address the problem of S. aureus infection recalcitrance by identifying the in vivo mechanism of persister formation in patients, examining how it contributes to antibiotic resistance and identifying therapeutic approaches to inhibit the induction of persisters and improve the outcome of antibiotic therapy.

摘要摘要众所周知，金黄色葡萄球菌感染很难用抗生素治疗。与许多革兰器不同 - 阴性病原体，其中治疗失败的风险与抗生素扩散的增加有关抗性和泛抗分离株的出现，金黄色葡萄球菌在很大程度上仍然容易受到多种影响抗生素。但是，目的地明显敏感，这些抗生素治疗经常失败，有20,000 人们于2017年在美国的金黄色葡萄球菌感染中死亡。金黄色葡萄球菌具有良好的吞噬作用，巨噬细胞的吞噬体是在感染过程中，越来越多地成为金黄色葡萄球菌细胞的主要储层。我们发现，在村里全身感染的模型，金黄色葡萄球菌不仅在巨噬细胞中生存，而且还进入多饮在这个利基市场中宽容，持久的状态，使其用抗生素无法治疗。我们的总体假设是巨噬细胞。金黄色的相互作用正在推动抗生素治疗失败患者。为此，在AIM 1中，我们将使用临床S. 金黄色的分离株和患者匹配的巨噬细胞，从外周血单核细胞中培养来自Vance Fowler博士的Aureus S. Aureus细菌组（SABG）的患者。我们还将检查是否抗生素巨噬细胞在组织培养中诱导的耐受性可以预测患者的预后。在AIM 2中，我们将检查呼吸爆发是否也能够在组织培养和鼠类细菌模型。呼吸爆发产生的ROS的双重能力诱导抗生素耐受性和诱变为抗生素进化创造了理想的环境感染期间的抗性。在AIM 3中，我们将研究2种治疗方法的潜力，以降低抗生素耐受性巨噬细胞的诱导。首先，我们将应用一系列抗氧化剂，包括最新的方法涉及专门针对巨噬细胞的治疗剂的目标递送。其次，我们将诱导M2 巨噬细胞的极化以减少ROS的产生并改善吞噬细胞的抗生素易感性 S.金黄色葡萄酒。总的来说，我们的提议有望通过识别来解决金黄色葡萄球菌感染的问题患者持续形成的体内机制，检查其如何促进抗生素耐药性并确定治疗方法来抑制持久的诱因并改善抗生素疗法。