Development Of New Chemotherapeutics For Tuberculosis

结核病新化疗药物的开发

• 批准号: 7592197
• 负责人: Clifton Barry
• 金额: $ 681.13万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592197
• 关键词: Active Sites; Affinity; Anabolism; Animals; Antibiotic Therapy; Area; Bacteria; Bacterial Typing; Binding; Biochemical; Biological; Biological Factors; Biological Process; Biology; Carbon; Cell Wall; Chemicals; Chemistry; Collaborations; Collection; Complex; Development; Drug Design; Enzymatic Biochemistry; Enzymes; Escherichia coli; Evaluation; Family; Family member; Fatty Acids; Fatty-acid synthase; Genus Mycobacterium; Goals; Growth; Human; Infection; Institutes; Iron; Lead; Ligands; Maps; Minnesota; Molecular Target; Molecular Weight; Mycobacterium tuberculosis; Mycolic Acid; Nitroimidazoles; Nocardia; Nuclear; Pathway interactions; Penicillins; Peptidyltransferase; Phase II Clinical Trials; Role; Science; Scientist; Siderophores; Soil; Staging; Structure; Synthesis Chemistry; System; Testing; Thinking; Triclosan; Tropical Disease; Tuberculosis; Work; analog; beta-Lactam Resistance; cell envelope; chemical synthesis; concept; drug development; fatty acid metabolism; fatty acid synthase II; functional group; hydroxy fatty acid; improved; in vivo; inhibitor/antagonist; interest; isoniazid; mycobacterial; mycobactins; novel; pre-clinical; preclinical study; thiolactomycin; tool; tuberculosis treatment

Currently this project focusses on four key areas: (1) the chemical synthesis of derivatives of a natural product that targets an enzyme involved in the biosynthesis of the mycobacterial cell wall called thiolactomycin, and (2) the chemical synthesis of analogs of nitroimidazoles such as PA-824, (3) the synthesis and evaluation of inhibitors of synthesis of the mycobacterial siderophore, Mycobactin, and (4) the synthesis and evaluation of substrates for, and inhibitors of, transpeptidases that are responsible for remodeling the TB cell envelope. Project (1) targets mycolic acids which are complex alpha-branched, beta-hydroxy fatty acids that are unique to mycobacteria which are heavily modified by a variety of functional groups. Mycolic acids are biosynthetically produced through an extension of normal fatty acid metabolism. In mycobacteria this is initiated by a "eukaryotic"-like Type I fatty acid synthase, a large multifunctional enzyme that produces primarily short-chain (16-24 carbons) fatty acids that are then substrates for a second fatty acid synthase system that is more typically associated with bacteria. This Type II system appears to be the molecular target for isoniazid as well as other inhibitors such as triclosan. Thiolactomycin is a low molecular weight natural product isolated from a soil Nocardia species that specifically inhibits one component of the bacterial Type II fatty acid synthase system. Although it is a modest inhibitor against most bacteria it has shown in vivo activity in various experimental infections of animals. Following on our structural studies of TLM in which we determined the co-crystal structure of two of our semisynthetic analogs with the homologous enzyme from E. coli we have been working with our collaborators at Stoneybrook to map active-site distances using an approach involving looking for interligand Nuclear Overhauser effects. We have synthesized several potential novel ligands and have been successful at observing such distance-dependent effect which are being used to improve the binding affinity of the lead molecule for the emzyme target. In Project (2) we are synthesizing analogs of nitroimiadazooxazines and nitroimidazooxazoles related to PA-824. PA-824 is currently in Phase II studies in humans for the treatment of tuberculosis. Working with scientists at the Novartis Institute for Tropical Diseases, TBRS scientists have synthesized and characterized a large collection of analogs of these compounds and are advancing these through preclinical studies. In Project (3) we are evaluating approaches to the inhibition of the biosynthesis of the iron-acquiring siderophore of Mycobacterium tuberculosis, Mycobactin. In collaboration with scientists at the Unvieristy of Minnesota's Center for Drug Design we are testing inhibitors of one of the earliest biosynthetic steps in this biosynthetic pathway. Targetting iron acquisition builds upon a strong historical interest in TBRS in understanding the biosynthesis of this molecule which is required for bacterial growth during infection. In project (4) we are exploring the biological role of a unique family of L,D-transpeptidases that are thought to contribute to the inherent beta-lactam resistance of TB. By a combination of biochemical and chemical studies we have established the function of two of the five members of this family and we have synthesized a panel of inhibitors and substrates in the hopes of both elucidating the underlying biology/enzymology as well as developing proof of concept molecules for a TB-specific family of penicillin-like compounds.

目前，该项目侧重于四个关键领域：（1）天然产物衍生物的化学合成，所述天然产物靶向参与分枝杆菌细胞壁生物合成的酶，称为硫乳霉素，和（2）硝基咪唑类似物如PA-824的化学合成，（3）分枝杆菌铁载体合成抑制剂，分枝杆菌素的合成和评价，和（4）负责重塑TB细胞包膜的转肽酶的底物和抑制剂的合成和评价。 项目（1）针对分枝菌酸，分枝菌酸是复杂的α-分支的β-羟基脂肪酸，其是分枝杆菌所特有的，被各种官能团大量修饰。分枝菌酸是通过正常脂肪酸代谢的扩展生物合成产生的。在分枝杆菌中，这是由“真核”样I型脂肪酸合酶启动的，I型脂肪酸合酶是一种主要产生短链（16-24个碳）脂肪酸的大型多功能酶，然后短链脂肪酸是更典型地与细菌相关的第二脂肪酸合酶系统的底物。该II型系统似乎是异烟肼以及其他抑制剂（如三氯生）的分子靶点。硫代乳霉素是一种低分子量的天然产物，分离自土壤诺卡氏菌属物种，特异性抑制细菌II型脂肪酸合成酶系统的一种组分。虽然它是一种针对大多数细菌的适度抑制剂，但它在各种动物实验感染中显示出体内活性。 在我们对TLM的结构研究中，我们确定了两个我们的半合成类似物与来自E.大肠杆菌，我们一直在与我们的合作者在Stoneybrook映射活性位点的距离使用的方法，涉及寻找配体间的核Overhauser效应。我们已经合成了几种潜在的新型配体，并已成功地观察到这种距离依赖性效应，这些效应被用于提高铅分子对酶靶的结合亲和力。 在项目（2）中，我们正在合成与PA-824相关的硝基咪唑并恶嗪和硝基咪唑并恶唑的类似物。PA-824目前正处于人类治疗结核病的II期研究中。TBRS科学家与诺华热带疾病研究所的科学家合作，合成并表征了大量这些化合物的类似物，并正在通过临床前研究推进这些类似物。 在项目（3）中，我们正在评估抑制结核分枝杆菌铁载体（Mycobactin）生物合成的方法。我们与明尼苏达大学药物设计中心的科学家合作，正在测试这种生物合成途径中最早的生物合成步骤之一的抑制剂。靶向铁获取建立在TBRS在理解感染期间细菌生长所需的这种分子的生物合成方面的强烈历史兴趣之上。 在项目（4）中，我们正在探索一个独特的L，D-转肽酶家族的生物学作用，该家族被认为有助于结核病的固有β-内酰胺耐药性。通过生物化学和化学研究的结合，我们已经建立了这个家族的五个成员中的两个的功能，并且我们合成了一组抑制剂和底物，希望阐明潜在的生物学/酶学以及开发TB特异性青霉素样化合物家族的概念分子的证据。