Project 1

项目1

基本信息

批准号：
10224228
负责人：
Beth Fuchs
金额：
$ 47.15万
依托单位：
MIRIAM HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224228
关键词：
Abscess Affect Anti-Inflammatory Agents Antibiotics Antimicrobial Effect Antimicrobial Resistance Antioxidants Arthritis Auranofin Automobile Driving Bacteria Bacterial Infections Blood Caenorhabditis elegans Catheters Centers of Research Excellence Clinical Development Devices Dose Drug Compounding Drug Targeting Drug resistance Endocarditis Ensure Exhibits Exposure to FDA approved Focal Infection Glutathione Gram-Negative Bacteria Gram-Positive Bacteria Growth Health care facility Helicobacter pylori Herbal Medicine Hospitals Host Defense Hydrogels Hydrogen Peroxide Immunocompromised Host Indwelling Catheter Infection Infectious Skin Diseases Investigation Investigational Drugs Lead Libraries Link Long-Term Care Mediating Medical Medical Device Medicinal Herbs Metabolism Microbial Biofilms Modeling Molecular Target Mus NADP Natural Resistance Nematoda Operative Surgical Procedures Organism Osteomyelitis Persons Pharmaceutical Preparations Proteins Reactive Nitrogen Species Reactive Oxygen Species Resistance Resistance development Sepsis Site Staphylococcus aureus Staphylococcus aureus infection Stream Superbug Surveys System Systemic infection TXN gene Testing Therapeutic Toxic effect Translations Wound Infection antimicrobial antimicrobial drug clinical investigation drug candidate drug development drug efficacy effective therapy efficacy evaluation gut microbiota high throughput screening improved joint infection medical implant methicillin resistant Staphylococcus aureus minimal inhibitory concentration mouse model multi-drug resistant pathogen new therapeutic target novel pathogen pathogenic bacteria preclinical evaluation prevent repaired resistance mechanism screening self assembly small molecule thioredoxin reductase tool

项目摘要

Abstract. Staphylococcus aureus is a Gram-positive bacterium that is clinically prominent with new isolates emerging that exhibit drug resistance, making treatments challenging with the current drug arsenal. S. aureus is the most commonly recognized multi-drug resistant (MDR) pathogen and it often referred to as a “superbug”, methicillin resistant S. aureus (MRSA) being the most prominent. MRSA is no longer limited to medical hospitals and are rapidly transmitted from person to person. With the growing problem, there is concern about effective treatment, leading to a fervent need for new antimicrobials. Using Caenorhabditis elegans as an infection model, we performed a high throughput screen (HTS) to identify compounds with activity against S. aureus, particularly MRSA. Our investigation determined that the anti- inflammatory compound auranofin (an FDA approved drug) and the medicinal herb extract shikonin are able to improve survival of infected nematodes, exhibiting minimal inhibitory concentrations at 0.25 g/ml and 4 g/ml, respectively. To accommodate our investigations of auranofin and shikonin as potential new antimicrobial compounds against S. aureus, we will interrogate the molecular target of auranofin, examining the effects to the thioredoxin system, an essential antioxidant defense in many Gram-positive bacteria. Our examination will include a survey of clinical isolates and low dose exposure to these compounds to determine if bacteria have available resistance mechanisms or can develop resistance (aim 1). Our aim is to investigate the translation of TrxR targeted compounds to mammalian systems using mice as an infection model for S. aureus. We will determine the drug efficacy of our TrxR targeted compounds on S. aureus inhibition, evaluating systemic and local infections (aim 2). Further, to build a new class of thioredoxin system inhibitory antibiotics, we will engage an antibatcerial target specific screen to identify new compounds, enhancing our chances of finding a drugable compound (aim 3). Thus driving the investigation of auranofin, shikonin, and other TrxR inhibitory compounds toward use as a treatment option for specific bacterial infections.

抽象的。金黄色葡萄球菌是一种革兰氏阳性细菌，在新分离株上在临床上突出新兴的提取耐药性，使治疗对当前药物库挑战。 S.金黄色葡萄球菌是最常见的多药耐药性（MDR）病原体，通常被称为“超级咬”，耐甲氧西林的金黄色葡萄球菌（MRSA）是最突出的。 MRSA不再限于医疗医院并迅速从一个人到一个人传播。随着日益严重的问题，人们担心有效治疗，导致对新抗菌剂的急需。使用秀丽隐杆线虫作为感染模型，我们进行了高通量屏幕（HTS）鉴定具有针对金黄色葡萄球菌的活性的化合物，尤其是MRSA。我们的调查确定了抗炎症化合物Auranofin（FDA批准的药物）和医用草药提取物shikonin能够提高感染线虫的存活，在0.25G/mL和4G/mL时表现出最小的抑制浓度，为了容纳我们对Auranofin和Shikonin的投资，作为潜在的新抗菌剂针对金黄色葡萄球菌的化合物，我们将询问Auranofin的分子靶标，研究对 Thioredoxin system, an essential antioxidant defense in many Gram-positive bacteria.我们的考试意志包括对这些化合物的临床分离株和低剂量暴露的调查，以确定细菌是否具有可用的电阻机制或可以发展阻力（AIM 1）。我们的目的是研究使用小鼠将TRXR靶向化合物向哺乳动物系统的翻译作为金黄色葡萄球菌的感染模型。我们将确定我们的TRXR靶向化合物的药物效率。金黄色葡萄干抑制作用，评估全身感染和局部感染（AIM 2）。此外，要建立新的硫氧还蛋白系统抑制性抗生素，我们将与抗生素靶标的筛选一起识别新化合物，增加了我们找到可吸毒化合物的机会（AIM 3）。推动了对auranofin的调查， shikonin和其他TRXR抑制性化合物可作为特定细菌感染的治疗选择。