Targeting MraY: Synthesis and Validation of MraY Inhibitors

靶向 MraY：MraY 抑制剂的合成和验证

基本信息

批准号：
8072058
负责人：
Michio Kurosu
金额：
$ 37万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8072058
关键词：
AIDS/HIV problem Acids Acquired Immunodeficiency Syndrome Amikacin Amino Acids Amino Alcohols Anabolism Anti-Bacterial Agents Anti-HIV Agents Antibiotics Antimycobacterial Agents Antitubercular Agents Applications Grants Behavior Biological Biological Assay Biological Factors Capromycin Cell Line Cells Cessation of life Ciprofloxacin Clinical Combined Modality Therapy Complex Cycloserine Cytochrome P450 3A4 Depsipeptides Development Dose Drug Delivery Systems Drug Kinetics Drug resistance in tuberculosis Drug-sensitive Enzymes Ethambutol Ethionamide Evaluation Exhibits Fluorescent Probes Future Generations Genus Mycobacterium Glycopeptides Goals Gram-Positive Bacteria Grant HIV HIV Infections Highly Active Antiretroviral Therapy Hospitals In Vitro Industry Infection Kanamycin Knowledge Laboratory Research Lactams Lead Libraries Life Liver Microsomes Metabolic Modeling Monkeys Multi-Drug Resistance Multidrug-Resistant Tuberculosis Mus Mycobacterium tuberculosis Nucleosides Nucleotides Ofloxacin Patients Penicillin-Binding Proteins Peptidoglycan Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Polymers Population Positioning Attribute Prevention Protease Inhibitor Pyrazinamide RNA-Directed DNA Polymerase Relative (related person)Reporting Research Resistance Reverse Transcriptase Inhibitors Rifampin Route Safety Scientist Screening procedure Series Solutions Source Staphylococcus aureus Streptomyces Structure Time Toxic effect Tuberculosis Tunicamycin UDP-N-acetylmuramic acid pentapeptide Uridine Validation amphomycin analog antimicrobial base chemical property combat cytotoxicity design drug metabolism efficacy evaluation functional group fungus improved in vivo inhibitor/antagonist interest isoniazid kidney cell lipid I methicillin resistant Staphylococcus aureus mouse model novel p-Aminosalicylic Acid programs public health relevance resistant strain response stereochemistry sugar topical antibacterial treatment strategy tuberculosis drugs

项目摘要

DESCRIPTION (provided by applicant): A MraY inhibitor from a natural source, capuramycin, exhibited significant activity in vivo using M. tuberculosis mouse infection model. Muraymycins possess a common core structure of capuramycin, however, their structural diversity is observed in an acyclic complex depsipeptide moiety and the C5'-sugar-appended. Promising in vivo antibactericidal activity of muraymycin A1 against S. aureus was highlighted by the Wyeth-Research groups. Thus, it is of our interest to validate the efficacy of muraymycin A1 in vitro and in vivo against M. tuberculosis. However, the fungus strain (Streptomyces spp. LL-AA896) used to produce muraymycin A1 and any congeners are not available, and muraymycin A1 has to be synthesized for the in vitro compound profiling. Thus, we will establish the synthetic route for intact muraymycin A1 to obtain enough molecules (Specific Aim 1). Furthermore, medicinal chemistry programs of muraymycin A1 and capuramycin with an aim to improve the efficacy including pharmacokinetics are hampered by 1) the complexity of these structures, 2) difficulty in chemically modifying the desired positions selectively, and 3) no convenient assay against Mtb MraY enzyme including difficulty in obtaining enough MraY substrate, Park's nucleotide. We accomplished a scalable chemoenzymatic and total synthesis of Park's nucleotide and its fluorescent probe, and established a convenient MraY inhibitor assay using a cell envelop enriched fraction including MraY, MurG and decaprenylphosphate. In addition, over the past years we obtained extensive knowledge of synthetic accessibility of uridine-amino-alcohol containing molecules in solution or on the polymer- support. We will continue designing and synthesizing new uridine-amino-alcohol derivatives in order to identify the minimal and essential structures of muraymycins and capuramycin (Specific Aim 2). In vitro profiling of the generated molecules against Mtb MraY and drug-sensitive and -resistant M. tuberculosis will be performed at the CSU Mycobacteria Research Laboratory (Specific Aim 3). PUBLIC HEALTH RELEVANCE: Multidrug resistant Mycobacterium tuberculosis (MDR-TB) has occurred in hospitals and correctional facilities, and frequently in HIV-infected patient. Clinical responses of MDR- TB patient to currently available drugs have been poor, and in some cases there is no response at all. The long term goal of this grant submission is to develop new drug leads for MDR-TB.

描述（由申请人提供）：来自天然来源卡普拉霉素的MraY抑制剂在结核分枝杆菌小鼠感染模型中表现出显着的体内活性。 Muraymycins 具有 Capuramycin 的共同核心结构，然而，在无环复合缩酚肽部分和附加的 C5'-糖中观察到它们的结构多样性。惠氏研究小组强调了 Muraymycin A1 对金黄色葡萄球菌的体内抗菌活性。因此，我们有兴趣在体外和体内验证 Muraymycin A1 对抗结核分枝杆菌的功效。然而，用于生产穆雷霉素 A1 的真菌菌株（链霉菌属 LL-AA896）和任何同系物均不可用，并且必须合成穆雷霉素 A1 才能进行体外化合物分析。因此，我们将建立完整的穆雷霉素A1的合成路线以获得足够的分子（具体目标1）。此外，旨在提高功效（包括药代动力学）的穆雷霉素 A1 和卡普拉霉素的药物化学计划受到以下因素的阻碍：1）这些结构的复杂性，2）难以选择性地化学修饰所需位置，以及 3）没有针对 Mtb MraY 的便捷测定酶包括难以获得足够的MraY底物Park核苷酸。我们完成了 Park 核苷酸及其荧光探针的可扩展化学酶法和全合成，并使用包括 MraY、MurG 和十异戊二烯磷酸酯在内的细胞包膜富集组分建立了方便的 MraY 抑制剂测定法。此外，在过去的几年中，我们获得了关于溶液中或聚合物载体上含有尿苷-氨基-醇的分子的合成可及性的广泛知识。我们将继续设计和合成新的尿苷-氨基-醇衍生物，以鉴定穆雷霉素和卡普拉霉素的最小和基本结构（具体目标2）。将在科罗拉多州立大学分枝杆菌研究实验室（具体目标 3）对生成的 Mtb MraY 和药物敏感且耐药的结核分枝杆菌分子进行体外分析。公共卫生相关性：医院和惩教机构中已出现耐多药结核分枝杆菌 (MDR-TB)，且常见于 HIV 感染者。耐多药结核病患者对现有药物的临床反应较差，在某些情况下根本没有反应。此次拨款申请的长期目标是开发耐多药结核病的新药物。