Mitigating Resistance & Virulence in MRSA

描述（由申请人提供）：抗生素耐药性是微生物面对设计为杀微生物的化合物的内在或适应性基因型和表型反应的结果。这个问题对于在卫生保健和社区环境中出现的优先病原体耐甲氧西林金黄色葡萄球菌（MRSA）非常重要。为了应对这一挑战，我们正在采取创新的方向：发现和/或开发调节微生物而不是杀死它们的抗生素。通过创新的策略和方法，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，即双氟尼松（DIF）和苯基羟基苯甲酸（POHB）类似物可减轻MRSA的基因型和表型抗生素耐药性和毒力。反过来，这种作用增强了抗生素在体内和体外的疗效。我们的初步数据已经揭示了这些化合物调节的潜在毒力、耐药性和调控靶基因。重要的是，从我们的初步数据中得出的化合物是通过广泛的临床经验已知的，在人类中是安全且耐受性良好的，并且是fda批准的。此外，我们已经就这些化合物的新的和重新用途的抗mrsa用途建立了知识产权地位，这是加速临床开发和商业化的关键。我们的分析验证平台和程序是基于知识和数据驱动的，因此与更多随机和非集中的高通量化学库筛选相比，具有明显的优势。整合体内筛选组件将验证对最常见（皮肤/软组织）和最难治疗（器械相关）MRSA感染形式的有效性。我们将把最初的项目重点放在MRSA上，作为一种“概念验证”病原体。然而，我们的检测平台和概念应该可以很容易地适应其他MDR病原体，超出了这个应用范围。因此，我们的计划推动创新科学、试验优化和靶点验证，以及高效的里程碑驱动进展，以确定恢复或增强现有抗生素疗效的主要候选药物，同时减轻耐药性的出现。最终，该项目的结果旨在加速抗生素- pohb组合的临床前和临床研究，以改善人类危及生命的MRSA感染的治疗效果。这一战略极具吸引力，可立即适用于一个重大的公共卫生问题，为发现和开发全新抗生素所需的高昂时间和成本提供了一个现实的桥梁。

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.