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人死于耐甲氧西林金黄色葡萄球菌（MRSA）相关感染;这一数字占耐甲氧西林细菌引起的所有死亡人数的近一半。公 目前批准的抗菌药物正在失去与多重耐药病原体的斗争。毫无疑问，迫切需要新的抗菌剂和开发它们的新方法;然而，新的抗菌剂的开发变得越来越困难。重新利用FDA批准的药物，具有良好的毒理学和药理学特征，以在原始医学适应症范围之外寻找新的应用，是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发现非细菌的有效杀菌活性的基础上。 在一个实施方案中，本发明涉及抗微生物药物金诺芬（auranofin）、依布硒啉（ebselen）和FdUrd，其在适用的临床范围内针对高度多药耐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微生物剂来治疗MRSA感染将跨越药物开发过程，并节省多年的昂贵研究。事实上，金诺芬最近已被FDA授予治疗人类阿米巴病的新药地位，进一步验证了我们的方法。本申请的目的是进一步开发、优化和验证金诺芬、依布硒啉和FdUrd作为MRSA感染的潜在治疗药物。此外，我们将评估这些药物在小鼠伤口模型中的治疗效果，该模型非常接近人类糖尿病足溃疡的状况;预计这将推进慢性伤口护理的现有知识。 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，我们重新利用这些药物的工作应该会显著影响和通知其他研究人员重新利用其他治疗药物作为多药耐药病原体的可见治疗选择的努力。

 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.