Targeting MraY: Synthesis and Validation of MraY Inhibitors

靶向 MraY：MraY 抑制剂的合成和验证

• 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
• 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

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）：使用M.结核病小鼠感染模型。Muraymycins具有Capuramycin的共同核心结构，然而，在无环复合缩肽部分和附加的C5 '-糖中观察到它们的结构多样性。Muraymycin A1对S.金黄色葡萄球菌是由Wyeth研究小组强调的。因此，我们感兴趣的是验证村霉素A1在体外和体内对M.结核然而，真菌菌株（链霉菌属（Streptomyces spp.）LL-AA896）和任何同系物不可用，必须合成村霉素A1用于体外化合物分析。因此，我们将建立完整村霉素A1的合成路线，以获得足够的分子（特定目标1）。此外，以改善包括药代动力学在内的功效为目的的村霉素A1和卡普霉素的药物化学程序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酶的方便测定，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的化学酶促和全合成，并使用包括MraY、MurG和十异戊烯基磷酸的细胞包膜富集级分建立了方便的MraY抑制剂测定。此外，在过去几年中，我们获得了在溶液中或在聚合物载体上含尿苷-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，以确定muraymycins和capuramycin的最小和基本结构（具体目标2）。针对Mtb MraY和药物敏感性和耐药性M.将在CSU分枝杆菌研究实验室（具体目标3）进行结核病研究。 公共卫生相关性：多药耐药结核病（MDR-TB）是近年来在医院和劳教机构中发生的一种结核病，且多见于HIV感染者。耐多药结核病患者对现有药物的临床反应很差，在某些情况下根本没有反应。该资助申请的长期目标是开发耐多药结核病的新药先导。