Mitigating Resistance & Virulence in MRSA

减轻阻力

• 批准号: 9223793
• 负责人: Michael R Yeaman
• 金额: $ 39.41万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-05 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223793
• 关键词: Acetates; Address; Animal Model; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Bacteria; Benzoates; Binding; Biological Assay; Bypass; Catheters; Clinical; Clinical Research; Clinical Treatment; Combined Antibiotics; Community Healthcare; Daptomycin; Data; Development; Devices; Diflunisal; Disease; Drug Design; FDA approved; Face; Failure; Fibronectins; Gene Expression; Gene Targeting; Genes; Genetic; Genome; Goals; Growth; Halogens; Health; Healthcare; Housekeeping; Housekeeping Gene; Human; In Vitro; Industry; Infection; Infectious Skin Diseases; Instinct; Intellectual Property; Investments; Kinetics; Knowledge; Lead; Life; Measurable; Measures; Mediating; Methods; Microbe; Microbial Biofilms; Modeling; Multi-Drug Resistance; Outcome; Pathogenicity; Peptides; Pharmaceutical Preparations; Phenotype; Populations at Risk; Positioning Attribute; Production; Proteins; Public Health; Resistance; Science; Skin; Specificity; Staphylococcus aureus; Structure; Time; Translating; Treatment Failure; Treatment outcome; United States National Institutes of Health; Validation; Vancomycin Resistance; Vancomycin-resistant S. aureus; Virulence; Virulence Factors; Work; analog; attributable mortality; commercialization; community setting; cost; design; experience; hydroxybenzoate; improved; in vivo; innovation; killings; knowledge base; meetings; methicillin resistant Staphylococcus aureus; microbial; microbicide; multi-drug resistant pathogen; next generation; novel; pathogen; pre-clinical; prevent; programs; public health priorities; research and development; response; screening; small molecule libraries; soft tissue

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.

描述（由申请人提供）：抗生素耐药性是固有或适应性的基因型和表型反应的结果，而微生物面临着旨在呈杀菌剂的化合物。对于优先病原体，耐甲氧西林的金黄色葡萄球菌（MRSA），该问题非常重要，该葡萄球菌（MRSA）在医疗保健和社区环境中出现。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，以及使用明确定义的可量化里程碑，我们的项目利用了我们令人兴奋的发现，即减轻了基因型和表型抗生素抗生素和MRSA中的苯基羟基苯甲酸酯（POHB）类似物。反过来，这种作用在体外和体内增强了抗生素功效。我们的初步数据已经揭示了这些化合物调节的潜在毒力，抗性和调节靶基因。重要的是，通过广泛的临床经验而闻名，从我们的初步数据中出现的化合物，可以在人类中安全且耐受性良好，并且经FDA批准。此外，我们已经建立了有关这些化合物的新的和重新利用的抗MRSA用途的知识产权地位，这是加速临床开发和商业化的关键。我们的测定验证平台和程序是基于知识和数据驱动的，因此比更随机且未加注的高吞吐量化学库屏幕具有明显的优势。体内筛选成分的整合将验证MRSA感染的最普遍（皮肤 /软组织）和最难治疗（与设备相关的）FOM中的功效。我们将将初始程序集中在MRSA上，作为“概念证明”病原体。但是，我们的测定平台和概念应易于适应以超出该应用程序范围的其他MDR病原体。因此，我们的计划推动了创新的科学，测定优化和目标验证以及有效的里程碑驱动的进步，以识别恢复或增强现有抗生素功效的主要候选者，同时减轻抵抗的出现。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，以改善人类威胁生命的MRSA感染的治疗结果。该策略具有很高的吸引力，并立即适用于一个重大的公共卫生问题，为从头开始的全新抗生素的发现时间和成本和开发的逼真的时间和成本提供了逼真的桥梁。