Mitigating Resistance & Virulence in MRSA

描述(由申请人提供)：抗生素耐药性是面对被设计为杀微生物剂的化合物的微生物固有的或适应性的基因和表型反应的结果。这个问题对优先病原体--耐甲氧西林金黄色葡萄球菌(MRSA)非常重要，它已经出现在医疗保健和社区环境中。为了迎接这一挑战，我们正在走一条创新的道路：发现和/或开发调节微生物的抗生素，而不是杀死它们。通过创新的战略和方法，以及使用定义明确、可量化的里程碑，我们的项目利用了我们令人兴奋的发现，即二氟尼柳(DIF)及其苯羟基苯甲酸酯(POHB)类似物减少了MRSA中基因和表型的抗生素耐药性和毒力。反过来，这一效应在体外和体内都能增强抗生素的效力。我们的初步数据已经揭示了这些化合物调节的潜在毒力、抗性和调控靶基因。重要的是，从我们的初步数据中出现的作为先导的化合物，通过广泛的临床经验已知在人类中是安全和耐受性良好的，并且是FDA批准的。此外，我们已经在这些化合物的新的和重新定位的抗MRSA用途方面建立了知识产权地位，这是加快临床开发和商业化的关键。我们的化验验证平台和程序是基于知识和数据驱动的，因此与更随机和无重点的高通量化学库筛选相比具有明显的优势。体内筛选组件的集成将验证对MRSA感染最普遍(皮肤/软组织)和最难治疗(与设备相关)的症状的有效性。我们将把最初的计划重点放在MRSA作为一种“概念验证”病原体上。然而，我们的检测平台和概念应该很容易适应于针对超出本应用范围的其他MDR病原体。因此，我们的计划推动创新科学、化验优化和靶向验证，以及有效的里程碑驱动的进展，以确定恢复或增强现有抗生素效力的主要候选药物，同时减少耐药性的出现。最终，该项目的结果旨在加快抗生素-POHB组合的临床前和临床研究，以改善威胁人类生命的MRSA感染的治疗结果。这一战略极具吸引力，并立即适用于一个重大的公共卫生问题，为新发现和开发全新抗生素提供了一座现实的桥梁，其时间和成本令人望而却步。

DESCRIPTION (provided by applicant): Antibiotic resistance is a result of intrinsic or adaptive genotypic and phenotypic responses of microbes that face compounds designed to be microbicidal. This problem is highly significant for the priority pathogen, methicillin-resistant Staphylococcus aureus (MRSA), which has emerged in healthcare as well as community settings. To meet this challenge, we are taking an innovative direction: discover and/or develop antibiotics that modulate microbes rather than kill them. Through innovative strategies and methods, and use of well-defined, quantifiable milestones our project leverages our exciting discovery that diflunisal (DIF) and phenyl-hydroxybenzoate (POHB) analogues thereof mitigate genotypic and phenotypic antibiotic resistance and virulence in MRSA. In turn, this effect enhances antibiotic efficacy in vitro and in vivo. Our Preliminary Data have already revealed potential virulence, resistance, and regulatory target genes modulated by these compounds. Importantly, compounds emerging as leads from our preliminary data are known via extensive clinical experience to be safe and well-tolerated in humans, and are FDA-approved. Moreover, we have already established an intellectual property position with respect to new and repurposed anti-MRSA uses of these compounds, a key to accelerating clinical development and commercialization. Our assay validation platform and program is knowledge-based and data-driven, thereby having a distinct advantage over more random and unfocused high throughput chemical library screens. Integration of an in vivo screen component will validate efficacy in the most prevalent (skin / soft tissue) and most difficult-to-treat (device-related) foms of MRSA infection. We will focus our initial program on MRSA as a "proof-of-concept" pathogen. However, our assay platform and concepts should be readily adaptable to target other MDR pathogens beyond the scope of this application. Thus, our plan drives innovative science, assay optimization and target validation, and efficient milestone-driven progress to identify lead candidates that restore or enhance efficacy of existing antibiotics, while mitigating emergence of resistance. Ultimately, results from this project are intended to accelerate pre-clinical and clinial studies of antibiotic-POHB combinations to improve treatment outcomes in life-threatening MRSA infections in humans. This strategy is highly attractive and immediately applies to a significant public health issue, affording a realistic bridge to the prohibitive time and cost of discovery and development of entirely new antibiotics de novo.