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Repurposing auranofin as antimicrobial to treat staphylococcal infections

将金诺芬重新用作抗菌剂来治疗葡萄球菌感染

基本信息

批准号：
9117837
负责人：
Mohamed Seleem
金额：
$ 37.63万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9117837
关键词：
Amebiasis Animal Model Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Antibiotic Resistance Antibiotics Auranofin Bacteria Bacterial Proteins Caring Centers for Disease Control and Prevention (U.S.)Cessation of life Chronic Clinical Clinical Trials Data Decubitus ulcer Development Diabetic Foot Ulcer Dose FDA approved Floxuridine Foundations Goals Grant Healed Health Human Infection Infectious Skin Diseases Inflammatory Response Knowledge Label Lead Maps Medical Methods Microbial Biofilms Mitochondrial Proteins Modality Modeling Multi-Drug Resistance Mus Oral Orphan Drugs Pharmaceutical Preparations Pharmacology and Toxicology Process Production Protein Biosynthesis Public Health Reporting Research Research Personnel Resistance Risk Staphylococcal Infections Staphylococcus aureus Testing Therapeutic Agents Time Toxin Treatment Efficacy Uncertainty United States Work antimicrobial antimicrobial drug bactericide comparative efficacy cost diabetic disorder prevention drug development drug discovery drug efficacy ebselen efficacy testing fight against healing innovation methicillin resistant Staphylococcus aureus multi-drug resistant pathogen mutant novel novel strategies pathogen pre-clinical pressure research study wound

项目摘要

DESCRIPTION (provided by applicant): Nearly 11,000 people died last year alone from a methicillin-resistant Staphylococcus aureus (MRSA)-related infection in the United States; this figure represents nearly half of all fatalities caused by antibiotic-resistant bacteria. It is well established that currently approved antimicrobials are losing the battle in the fight against multidrug-resistant pathogens. Without a doubt, novel antimicrobials and novel approaches to develop them are urgently needed; however, new antimicrobials are becoming increasingly difficult to develop. Repurposing FDA-approved drugs, with well-characterized toxicology and pharmacology, to find new applications outside the scope of the original medical indication is a novel way to reduce both the time and cost associated with antimicrobial innovation. Studies proposed in this application build upon discoveries of the potent bactericidal activity of the non- antimicrobial drugs auranofin, ebselen and FdUrd, in an applicable clinical range, against highly multidrug- resistant Gram-positive pathogens, including MRSA. Our preliminary studies strongly suggest that repurposing these drugs as an antimicrobial agent to treat MRSA infections will leapfrog the drug development process and save years of expensive research. The fact that auranofin recently has been granted orphan-drug status from the FDA for treatment of human amebiasis, further validates our approach. The goal of this application is to further develop, optimize, and validate auranofin, ebselen, and FdUrd as potential treatment for MRSA infections. In addition, we will evaluate the therapeutic efficacy of these drugs in a mouse wound-model that closely approximates the condition of diabetic foot ulcers in humans; this is expected to advance current knowledge in chronic wound care. Our findings in MRSA will be broadly relevant to other important pathogens impacting global public health. Furthermore, our work to repurpose these drugs should significantly impact and inform efforts by other researchers to repurpose other therapeutic agents as visible treatment options for multidrug-resistant pathogens.

描述(由申请人提供)：仅去年一年，美国就有近11,000人死于与甲氧西林耐药金黄色葡萄球菌(MRSA)相关的感染；这一数字占耐药细菌造成的所有死亡人数的近一半。这很好已经确定，目前批准的抗菌素在与多重耐药病原体的斗争中正在输掉这场战斗。毫无疑问，迫切需要新的抗菌剂和开发它们的新方法；然而，开发新的抗菌剂正变得越来越困难。改变FDA批准的具有良好毒理学和药理学特征的药物的用途，以寻找原始医学适应症范围之外的新应用，是一种减少与抗菌药物创新相关的时间和成本的新方法。在本申请中提出的研究建立在对非... 抗菌药物Auranofin、ebselen和FdUrd，在临床适用范围内，对高度耐多药的革兰氏阳性病原体，包括MRSA。我们的初步研究强烈表明，将这些药物重新用作抗菌剂来治疗MRSA感染将跨越药物开发过程，并节省多年昂贵的研究。Auranofin最近被FDA批准为治疗人类阿米巴病的孤儿药物，这一事实进一步验证了我们的方法。该应用程序的目标是进一步开发、优化和验证Auranofin、ebselen和FdUrd作为治疗MRSA感染的潜在药物。此外，我们将在接近人类糖尿病足部溃疡情况的小鼠伤口模型中评估这些药物的治疗效果；这有望促进目前对慢性伤口护理的了解。我们在MRSA中的发现将与影响全球公共卫生的其他重要病原体广泛相关。此外，我们重新调整这些药物用途的工作应该会对其他研究人员重新调整其他治疗药物作为治疗多重耐药病原体的可见选择的努力产生重大影响，并为其提供信息。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

In Vitro Antibacterial Activity of Rhodanine Derivatives against Pathogenic Clinical Isolates.

DOI：
10.1371/journal.pone.0164227
发表时间：
2016
期刊：
PloS one
影响因子：
3.7
作者：
AbdelKhalek A;Ashby CR Jr;Patel BA;Talele TT;Seleem MN
通讯作者：
Seleem MN

In Vitro Screening of an FDA-Approved Library Against ESKAPE Pathogens.

DOI：
10.2174/1381612823666170209154745
发表时间：
2017
期刊：
Current pharmaceutical design
影响因子：
3.1
作者：
Younis W;AbdelKhalek A;Mayhoub AS;Seleem MN
通讯作者：
Seleem MN

Drug repurposing for the treatment of staphylococcal infections.

DOI：
10.2174/1381612821666150310104416
发表时间：
2015
期刊：
Current pharmaceutical design
影响因子：
3.1
作者：
Thangamani S;Mohammad H;Younis W;Seleem MN
通讯作者：
Seleem MN

Evaluation of short synthetic antimicrobial peptides for treatment of drug-resistant and intracellular Staphylococcus aureus.

DOI：
10.1038/srep29707
发表时间：
2016-07-11
期刊：
Scientific reports
影响因子：
4.6
作者：
Mohamed MF;Abdelkhalek A;Seleem MN
通讯作者：
Seleem MN

Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens.

DOI：
10.1038/srep22571
发表时间：
2016-03-03
期刊：
Scientific reports
影响因子：
4.6
作者：
Thangamani S;Mohammad H;Abushahba MF;Sobreira TJ;Hedrick VE;Paul LN;Seleem MN
通讯作者：
Seleem MN