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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革兰氏阳性细菌，临床突出的新分离株