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。阴性病原体，其中治疗失败的风险与抗生素的日益传播有关抗性和泛抗性分离株的出现，金黄色葡萄球菌仍然很容易受到多种然而，尽管有明显的敏感性，这些抗生素治疗经常失败，并且 20,000 2017 年，美国有人死于金黄色葡萄球菌感染。金黄色葡萄球菌有能力在吞噬作用中生存，巨噬细胞的吞噬溶酶体是我们发现，在小鼠体内，金黄色葡萄球菌细胞是感染过程中的主要储存库。在全身感染模型中，金黄色葡萄球菌不仅在巨噬细胞内存活，而且进入多药体内该生态位内存在耐受、持续的状态，使其无法用抗生素治疗。我们的总体假设是巨噬细胞-金黄色葡萄球菌相互作用导致抗生素治疗失败。患者。为了测试这一点，在目标 1 中，我们将使用临床金黄色葡萄球菌检查宿主巨噬细胞诱导的抗生素耐受性。从外周血单核细胞中培养的金黄色葡萄球菌分离株和患者匹配的巨噬细胞我们还将检查是否使用了抗生素。组织培养中巨噬细胞的耐受诱导可以预测患者的结果。在目标 2 中，我们将检查呼吸爆发是否也能够在体内产生抗生素抗性细胞。组织培养和鼠菌血症模型中呼吸爆发产生的ROS的双重能力。诱导抗生素耐受性和诱变为抗生素的进化创造了理想的环境感染期间的抵抗力。在目标 3 中，我们将研究 2 种治疗方法降低抗生素耐受性的潜力首先，我们将应用一系列抗氧化剂，包括最先进的方法。其次，我们将诱导M2 巨噬细胞极化以减少ROS产生并提高吞噬细胞的抗生素敏感性金黄色葡萄球菌。总之，我们的提案承诺通过识别金黄色葡萄球菌感染顽固性问题来解决患者体内持久形成机制，检查其如何导致抗生素耐药性并确定抑制持久性诱导并改善结果的治疗方法抗生素治疗。