Broad-Spectrum Antimicrobials Targeting the D-Alanine Pathway

针对 D-丙氨酸途径的广谱抗菌药物

• 批准号: 8501252
• 负责人: KAREN G. ANTHONY
• 金额: $ 160.54万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501252
• 关键词: Academia; Address; Alanine; Alanine Racemase; Animal Disease Models; Animal Model; Anthrax disease; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Area; Bacillus anthracis; Bacteremia; Bacteria; Bacterial Infections; Biochemical; Biological; Biological Assay; Cell Wall; Characteristics; Chemical Structure; Clinical; Coupled; Cycloserine; Development; Ensure; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzyme Interaction; Enzymes; Exposure to; Goals; Human; Industry; Infection; Instruction; Lead; Life; Metabolic Pathway; Methods; Microbial Drug Resistance; Modeling; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Nature; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Public Health; Qualifying; Readiness; Recombinants; Research; Research Personnel; Resistance development; Specificity; Staphylococcus aureus; Strategic Planning; Therapeutic; TimeLine; Toxic effect; Treatment Efficacy; Tuberculosis; Vendor; Vision; antimicrobial; antimicrobial drug; biodefense; commercialization; design; genetic analysis; high throughput screening; improved; inhibitor/antagonist; interest; methicillin resistant Staphylococcus aureus; mouse model; multidisciplinary; novel; pathogen; pharmacophore; pre-clinical; prevent; programs; resistance mechanism; response; screening; small molecule; structural biology; success; therapeutic target

DESCRIPTION (provided by applicant): In response to NIAID's Strategic Plan for Biodefense Research, we have initiated a program to discover and develop broad-spectrum antimicrobials that target multiple bacterial pathogens through inhibition of alanine racemase, an enzyme in the D-alanine metabolic pathway that is essential for bacterial cell wall synthesis. This pathway is highly conserved in bacteria, virtually absent in humans, and is a validated target of cycloserine, a commercially available antibiotic that is limited by off-target toxicity. The long-term goal of this project is to develop safe and effective small molecule therapeutics that target alanine racemase in a variety of bacterial pathogens including those of biodefense importance. A proprietary high-throughput screening assay using recombinant Mycobacterium tuberculosis alanine racemase was developed to screen for novel enzyme inhibitors. A pilot screen identified promising 'hits' with antibacterial activity against M. tuberculosis, the bacterium that causes tuberculosis. At least one of these hits inhibits clinical isolates that are multi-drug resistant (MDRTB). This project will broaden the number and utility of our alanine racemase inhibitors as anti-infectives effective against multiple NIAID bacterial priority pathogens. Starting with hit compounds active against MDRTB, iterative medicinal chemistry and screening will be used to broaden the spectrum of activity of these agents against Bacillus anthracis, the causative agent of anthrax, and methicillin-resistant Staphylococcus aureus (MRSA), the causative agent of life threatening bacteremia. This project will be performed by a multidisciplinary team of investigators from academia and industry with expertise encompassing such areas as high-throughput screening, small molecule medicinal chemistry, and structural biology who share a vision of a novel broad-spectrum alanine racemase inhibitor as a therapeutic against multiple bacterial pathogens. This project will employ methods of high-throughput screening and medicinal chemistry coupled with structural biology and animal models of MDR-TB, MRSA and anthrax to advance screening hits towards therapeutic leads. RELEVANCE (See instructions): The long-term product goal of this project is a broad-spectrum therapeutic to treat bacterial infections of public health and biodefense importance. Accomplishing this goal would enhance our national preparedness for natural, accidental and intentional exposure to several pathogens, and help address emerging microbial drug resistance.

描述（由申请人提供）：为了响应Niaid的生物化研究战略计划，我们启动了一项计划，旨在发现和开发广谱抗菌剂，该抗微生物剂通过抑制丙氨酸丙氨酸种族酶（抑制D-丙氨酸代谢途径中的酶，这是细菌细胞孔壁合成的必不可少的必不可少的细菌病原体）。该途径在细菌中是高度保守的，实际上在人类中没有，并且是环丝氨酸的验证靶标，这是一种可获得市售的抗生素，受到脱靶毒性的限制。该项目的长期目标是开发安全有效的小分子疗法，这些疗法靶向各种细菌病原体（包括生物浓度重要性的细菌病原体）。使用重组结核分枝杆菌丙氨酸种族酶进行专有的高通量筛查测定法，以筛选新的酶抑制剂。试点屏幕鉴定出具有抗菌活性对结核分枝杆菌的有希望的“命中”，这是导致结核病的细菌。这些命中中至少有一个抑制了耐多药物（MDRTB）的临床分离株。该项目将扩大我们的丙氨酸种族酶抑制剂的数量和效用，作为针对多种尼亚德细菌优先病原体有效的抗感染剂。从对MDRTB进行活跃的HIT化合物开始，迭代药物化学和筛选将用于扩大这些药物对炭疽芽孢杆菌的活性谱，炭疽的病毒剂和耐甲氧西林的葡萄球菌金黄色葡萄球菌（MRSA）（MRSA）（MRSA），威胁性生命的生命危险性葡萄球菌。该项目将由来自学术界和行业的研究人员组成的多学科团队，其专业知识包括诸如高通量筛查，小分子药物化学和结构生物学等领域，他们对新型广谱丙氨酸丙氨酸种族歧视剂抑制剂的愿景是针对多种细菌病原体的治疗方法。该项目将采用高通量筛查和药物化学的方法以及MDR-TB，MRSA和炭疽的结构生物学和动物模型，以推动对治疗铅的筛查。相关性（请参阅说明）：该项目的长期产品目标是一种广泛的治疗方法，可治疗对公共卫生和生物影响力重要性的细菌感染。实现这一目标将增强我们对几种病原体的自然，意外和故意暴露的全国准备，并有助于解决新兴的微生物耐药性。