Biosynthesis and medicinal chemistry of the capuramycin antimycobacterial antibiotics

辣椒霉素抗分枝杆菌抗生素的生物合成和药物化学

• 批准号: 9246017
• 负责人: Jon Scott Thorson
• 金额: $ 20万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246017
• 关键词: Achievement; Acids; Address; Anabolism; Antibiotics; Antimycobacterial Agents; Antitubercular Agents; Applied Research; Biological; Biological Availability; Cell Wall; Cessation of life; Chemicals; China; Clinical; Collaborations; Communicable Diseases; Country; Development; Disease; Drug resistance; Drug resistance in tuberculosis; Engineering; Enzymes; Family; Fostering; Funding Mechanisms; Future; Goals; Health; Hexuronic Acids; Human; In Vitro; Incidence; India; Individual; Lead; Libraries; Modification; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Natural Products; Nucleosides; Open Reading Frames; Peptidoglycan; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phosphotransferases; Population; Preparation; Production; Property; Reaction; Recovery; Reporting; Research; Resistance; Rifampin; Series; Source; Structure; Substrate Specificity; Sugar Substitute; System; Technology; Therapeutic; Toxic effect; Treatment Protocols; Tuberculosis; United States; Uridine; World Health Organization; analog; bactericide; chemical function; clinical development; drug development; drug discovery; extensive drug resistance; fighting; fundamental research; glycosyltransferase; improved; in vitro activity; in vivo; inhibitor/antagonist; innovation; isoniazid; killings; nanomolar; novel; pathogen; permissiveness; pharmacophore; resistance mechanism; resistant strain; scaffold; sugar; tool; translocase; tuberculosis drugs; tuberculosis treatment; virtual

Tuberculosis (TB)—which is primarily caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb)—is an ancient disease that remains one of the deadliest communicable diseases worldwide. A paramount concern heading into the future is the rapid rise in drug-resistant TB. The World Health Organization estimated 480,000 cases of TB with 190,000 deaths in 2014 with resistance to the first-line anti-TB drugs isoniazid and rifampicin. Furthermore, totally drug-resistant Mtb has now been documented in multiple countries including the United States. The capuramycin family of glycosylated nucleoside antibiotics are excellent candidates for anti-TB drug discovery and development because they (i) are considered new chemical entities with several unusual structural features compared to all antibiotics including clinical anti-TB drugs, (ii) target a novel and essential enzyme (translocase 1; TL1) in cell wall biosynthesis, (ii) have exceptional anti-Mtb activity in vitro and in vivo, (iv) are bactericidal and kill Mtb faster than any first-line anti-TB drug in vitro, and (v) have no toxicity. Our primary objectives in this proposal are to define a biosynthetic mechanism for the assembly of the unusual unsaturated hexuronic acid component in capuramycins (Aim 1) and establish complementary chemical (via neoglycorandomization; Aim 2) and biosynthetic (via native and nonnative glycosyltransferases; Aim 3) platforms for rapidly generating novel hexuronic acid-substituted capuramycins that can be screened for TL1 inhibition, anti-Mtb activity, and improved pharmacological properties. Additionally, these novel capuramycin analogues will be screened as potential substrates or inhibitors of the phosphotransferase CapP, which covalently modifies capuramycin as a strategy of self-resistance within the producing strain and is potentially a widespread resistance mechanism. It is expected that, upon completion of the aims, a new biosynthetic mechanism for sugar incorporation and modification will be defined. Furthermore, the completion of the aims will provide the first practical, comprehensive strategy to rapidly interrogate/modulate the fundamental features of capuramycin core pharmacophore, which will not only be important for the clinical development of capuramycin but can be applied to other glycosylated nucleoside antibiotics, of which dozens are now known with diverse biological activities.

结核病（TB）——主要由细菌病原体结核分枝杆菌（Mtb）引起——是 这是一种古老的疾病，至今仍然是全世界最致命的传染病之一。最关心的问题 展望未来，耐药结核病将迅速增加。世界卫生组织估计有 480,000 2014年，一线抗结核药物异烟肼和利福平耐药的结核病病例导致19万例死亡。 此外，包括美国在内的多个国家现已记录到完全耐药的结核分枝杆菌。 国家。糖基化核苷抗生素Capuramycin家族是抗结核药物的优秀候选者 发现和开发，因为它们（i）被认为是具有几个不寻常结构的新化学实体 与包括临床抗结核药物在内的所有抗生素相比，具有以下特点：(ii) 针对一种新型且必需的酶 （转位酶 1；TL1）在细胞壁生物合成中，(ii) 在体外和体内具有出色的抗 Mtb 活性，(iv) 体外杀菌和杀灭结核分枝杆菌的速度比任何一线抗结核药物都要快，并且 (v) 无毒性。我们的小学 该提案的目标是定义一种生物合成机制，用于组装不饱和脂肪酸 辣椒霉素中的己糖醛酸成分（目标 1）并建立补充化学物质（通过 新糖随机化；目标 2) 和生物合成（通过天然和非天然糖基转移酶；目标 3）平台 用于快速生成新型己糖醛酸取代的辣椒霉素，可筛选 TL1 抑制作用， 抗 Mtb 活性，并改善药理特性。此外，这些新型辣椒霉素类似物 将被筛选为磷酸转移酶 CapP 的潜在底物或抑制剂，该酶共价修饰 辣椒霉素作为生产菌株内的一种自我抵抗策略，并且可能是一种广泛传播的 抵抗机制。预计在完成这些目标后，将形成一种新的糖生物合成机制 将定义合并和修改。此外，目标的完成将提供第一个 快速询问/调节辣椒霉素核心基本特征的实用综合策略 药效团，这不仅对Capuramycin的临床开发很重要，而且可以应用 与其他糖基化核苷抗生素相比，目前已知其中有数十种具有不同的生物活性。