Project 1

项目1

• 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
• 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

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菌，临床上以新分离株为主 出现了耐药性，使目前的药物库的治疗具有挑战性。S.金黄色 最常见的多药耐药（MDR）病原体，通常被称为“超级细菌”， 耐甲氧西林金黄色葡萄金黄色葡萄球菌（MRSA）是最突出的。MRSA不再局限于医疗医院 并在人与人之间迅速传播。随着问题的日益严重，人们担心有效的 治疗，导致对新的抗菌药物的热切需求。 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S.金黄色葡萄球菌，特别是MRSA。我们的调查确定反- 炎性化合物金诺芬（FDA批准的药物）和药用草药提取物紫草素能够 提高受感染线虫的存活率，在0.25 μ g/ml和4 μ g/ml时表现出最小抑制浓度， 分别为了适应我们对金诺芬和紫草素作为潜在的新抗菌剂的研究， 化合物对S.金黄色葡萄球菌，我们将询问金诺芬的分子靶点，检查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菌的一种重要的抗氧化防御系统。我们的检查将 包括对临床分离物和低剂量暴露于这些化合物调查，以确定细菌是否 现有的耐药机制或可能产生耐药性（目标1）。 我们的目的是使用小鼠研究TrxR靶向化合物到哺乳动物系统的翻译 作为S.金黄色。我们将确定我们的TrxR靶向化合物对S. 金黄色葡萄球菌抑制，评价全身和局部感染（目的2）。此外，为了构建一类新的硫氧还蛋白， 系统抑制性抗生素，我们将进行抗细菌靶向特异性筛选以识别新化合物， 增加我们找到可药用化合物的机会（目标3）。从而推动了对金诺芬的研究， 紫草素和其他TrxR抑制化合物作为特定细菌感染的治疗选择。