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.

摘要：金黄色葡萄球菌是一种临床上突出的新分离株的革兰氏阳性细菌。出现耐药性，使得当前的金黄色葡萄球菌治疗具有挑战性。最常见的多重耐药（MDR）病原体，通常被称为“超级细菌”，耐甲氧西林金黄色葡萄球菌 (MRSA) 是最突出的，它不再局限于医疗医院。随着问题的日益严重，人们开始担心其有效性。治疗，导致对新抗菌药物的迫切需求。使用秀丽隐杆线虫作为感染模型，我们进行了高通量筛选（HTS）鉴定具有抗金黄色葡萄球菌活性的化合物，特别是耐甲氧西林金黄色葡萄球菌（MRSA）。炎症化合物金诺芬（FDA 批准的药物）和药草提取物紫草素能够提高受感染线虫的存活率，最低抑制浓度为 0.25 µg/ml 和 4 µg/ml，分别适应我们对金诺芬和紫草素作为潜在新型抗菌剂的研究。针对金黄色葡萄球菌的化合物，我们将探究金诺芬的分子靶标，检查其对金黄色葡萄球菌的影响硫氧还蛋白系统是许多革兰氏阳性细菌中重要的抗氧化防御系统。包括对临床分离株和低剂量接触这些化合物的调查，以确定细菌是否具有可用的耐药机制或可能产生耐药性（目标 1）。我们的目标是利用小鼠研究针对哺乳动物系统的 TrxR 化合物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 靶向化合物对金黄色葡萄球菌的药物功效。金黄色葡萄球菌抑制，评估全身和局部感染（目标 2）。系统抑制性抗生素，我们将进行抗菌靶点特异性筛选来识别新化合物，提高我们找到可成药化合物的机会（目标 3），从而推动金诺芬的研究，紫草素和其他 TrxR 抑制化合物可用作特定细菌感染的治疗选择。