Repurposing auranofin as antimicrobial to treat staphylococcal infections

 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。

 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.