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，至今仍是世界上最致命的传染病之一。一个最重要的问题 耐药结核病的迅速增加是未来的趋势。世界卫生组织估计， 2014年有19万人死于结核病，对一线抗结核药物异烟肼和利福平具有耐药性。 此外，在包括美国在内的多个国家， States.卡普霉素家族的糖基化核苷类抗生素是抗结核药物的优秀候选者 发现和发展，因为他们（i）被认为是新的化学实体与几个不寻常的结构 与包括临床抗结核药物在内的所有抗生素相比，（ii）靶向一种新的必需酶 （i）在细胞壁生物合成中具有显著的抗Mtb活性，（ii）在体外和体内具有显著的抗Mtb活性，（iv） 在体外杀菌和杀死Mtb比任何一线抗TB药物都快，和（v）没有毒性。我们的首要 该提案的目标是确定一种生物合成机制，用于组装不寻常的不饱和脂肪酸。 capuramycins中己糖醛酸组分（Aim 1）和建立补充化学物质（通过 新糖基化; Aim 2）和生物合成（通过天然和非天然糖基转移酶; Aim 3）平台 为了快速产生可筛选TL 1抑制的新的己糖醛酸取代的卡普拉霉素， 抗Mtb活性和改善的药理学性质。此外，这些新的卡普霉素类似物 将被筛选为磷酸转移酶CapP的潜在底物或抑制剂，其共价修饰 Capuramycin作为生产菌株内的自我抗性策略，并且可能是一种广泛的 抗性机制预计，在完成这些目标后， 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/调节卡普霉素核心基本特征的实用、全面的策略 药效团，这不仅对卡普霉素的临床开发很重要， 其他糖基化核苷抗生素，其中几十个现在已知具有不同的生物活性。