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: 8109403
• 负责人: KAREN G. ANTHONY
• 金额: $ 161.98万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109403
• 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; Screening procedure; 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; 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 的生物防御研究战略计划，我们启动了一项计划，旨在发现和开发广谱抗菌药物，通过抑制丙氨酸消旋酶（D-丙氨酸代谢途径中的一种酶）来靶向多种细菌病原体这对于细菌细胞壁的合成至关重要。该途径在细菌中高度保守，在人类中几乎不存在，并且是环丝氨酸的有效靶点，环丝氨酸是一种市售抗生素，但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，针对多种细菌病原体（包括具有生物防御重要性的细菌病原体）中的丙氨酸消旋酶。开发了一种使用重组结核分枝杆菌丙氨酸消旋酶的专有高通量筛选测定法来筛选新型酶抑制剂。初步筛选发现了对结核分枝杆菌（结核病细菌）具有抗菌活性的“热门产品”。这些打击中至少有一种能够抑制多重耐药（MDRTB）的临床分离株。该项目将扩大我们的丙氨酸消旋酶抑制剂作为抗感染药物的数量和用途，有效对抗多种 NIAID 细菌优先病原体。从具有抗 MDRTB 活性的热门化合物开始，迭代药物化学和筛选将用于拓宽这些药物针对炭疽杆菌（炭疽病病原体）和耐甲氧西林金黄色葡萄球菌（MRSA）（生命病原体）的活性谱。威胁菌血症。该项目将由来自学术界和工业界的多学科研究人员团队执行，他们拥有高通量筛选、小分子药物化学和结构生物学等领域的专业知识，他们对新型广谱丙氨酸消旋酶抑制剂作为治疗药物有着共同的愿景对抗多种细菌病原体。该项目将采用高通量筛选和药物化学方法，结合耐多药结核病、耐甲氧西林金黄色葡萄球菌和炭疽的结构生物学和动物模型，以推进治疗先导化合物的筛选。相关性（参见说明）：该项目的长期产品目标是一种广谱治疗药物，用于治疗对公共卫生和生物防御具有重要意义的细菌感染。实现这一目标将加强我们国家对自然、意外和故意接触多种病原体的准备，并有助于解决新出现的微生物耐药性。