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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。不像很多外国佬- 治疗失败的风险与抗生素传播增加相关的阴性病原体耐药性和泛耐药菌株的出现，金黄色葡萄球菌仍然对多重抗生素。然而，尽管有明显的敏感性，这些抗生素治疗经常失败，20,000 2017年，美国有人死于金黄色葡萄球菌感染。金黄色葡萄球菌具有很好的生存吞噬能力，巨噬细胞的吞噬酶体能越来越被认为是感染期间金黄色葡萄球菌细胞的主要储存库。我们发现，在一只老鼠身上全身感染模型，金黄色葡萄球菌不仅在巨噬细胞内存活，而且进入多药在这一利基中，耐受、持久的状态，使其无法用抗生素治疗。我们的总体假设是巨噬细胞-S。金黄色葡萄球菌的相互作用导致抗生素治疗失败病人。为了测试这一点，在目标1中，我们将使用临床S。金黄色葡萄球菌分离株和患者匹配的巨噬细胞，从取自外周血的单个核细胞培养来自Vance Fowler博士金黄色葡萄球菌菌血症组(SABG)的患者。我们还将检查抗生素是否巨噬细胞在组织培养中诱导耐受可以预测患者的预后。在目标2中，我们将检查呼吸爆发是否也能够在组织培养和小鼠菌血症模型。呼吸爆发产生的ROS的双重容量诱导抗生素耐受和突变为抗生素的进化创造了理想的环境在感染期间产生抵抗力。在目标3中，我们将研究减少抗生素耐受性的两种治疗方法的潜力。巨噬细胞的诱导。首先，我们将应用一系列抗氧化剂，包括最先进的方法涉及针对巨噬细胞的治疗药物的靶向输送。其次，我们将诱导M2 巨噬细胞极化以减少ROS的产生并提高吞噬细胞对抗生素的敏感性金黄色葡萄球菌。总而言之，我们的提案承诺通过确定患者体内永生化形成的机制，研究它如何导致抗生素耐药性以及确定治疗方法，以抑制持久者的诱导，并改善预后抗生素治疗。