Biosynthetic studies and development of ribomimetic-based anti-infectives

基于核糖体的抗感染药物的生物合成研究和开发

基本信息

批准号：
10318150
负责人：
TAIFO MAHMUD
金额：
$ 35.75万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-08 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318150
关键词：
4-Aminobenzoic Acid Acarbose Acyl Carrier Protein Acyltransferase Address Anabolism Animals Anti-Bacterial Agents Anti-Infective Agents Antibiotics Antidiabetic Drugs Antifungal Agents Antimalarials Antiparasitic Agents Antiviral Agents Bacteria Binding Proteins Biological Biological Assay Chemicals Chemistry Clinic Clinical Collaborations Communicable Diseases Data Development Enzymes Gene Silencing Genetic Gentamicins Goals Health Human In Vitro Institutes Investigation Knowledge Libraries Malaria Mediating Medical center Metabolic Biotransformation Natural Products Neomycin Oregon Oseltamivir Pactamycin Parasites Pathway interactions Pharmaceutical Preparations Plants Positioning Attribute Production Property Proteins Recombinants Research Ribose Scientific Advances and Accomplishments Skeleton Streptomyces Streptomycin Structure System Testing Toxic effect Translational Research Virus Work analog anti-hepatitis B anti-influenza anti-influenza drug antimicrobial antimicrobial drug base combat cytotoxicity drug discovery entecavir experience glycosylation glycosyltransferase high throughput screening holo-(acyl-carrier-protein) synthase improved in vitro activity insight mimetics multidisciplinary neplanocin A novel therapeutics polyketide synthase reconstitution research and development sugar thioester validamycins voglibose

项目摘要

PROJECT SUMMARY Sugar mimetics have long been known for their important biological activities. Many of them are currently used in clinics as antimicrobials (e.g., streptomycin, gentamycin, neomycin), antivirals (e.g., oseltamivir, peramivir, entecavir), and anti-diabetics (e.g., acarbose, voglibose). Among naturally-occurring sugar mimetics are the aminocyclopentitols, which contain a five-membered cyclitol unit resembling ribose (ribomimetics). However, due to their broad-spectrum toxicity and/or low production yield, none has yet been developed for clinical use. Therefore, addressing these limitations may provide new paths to the exploitation of their full potential as new drug leads. The long-term goals of this project are to understand the biosynthesis of ribomimetic natural products and to develop new ribomimetic-based drugs to combat infectious diseases. In this proposal, we will focus effort on interrogating the biosynthesis of the ribomimetic-containing antibiotic pactamycin and developing new pactamycin analogs as drug leads against bacteria, viruses, and malarial parasites. Our preliminary data suggest that formation of the pactamycin core structure involves highly unusual discrete polyketide synthases, a broad-spectrum glycosyltransferase, and a radical SAM enzyme. We also found that the tailoring pathway to pactamycin is exceptionally perplexing, due to the activity of numerous promiscuous tailoring enzymes. Furthermore, we have developed genetic, synthetic, and chemo-enzymatic strategies (involving a broad-spectrum ketoacyl-ACP synthase (KAS) III-like protein) to produce new pactamycin analogs and other ribomimetic compounds, some of which have improved biological properties. Here, we propose to: 1) characterize the coordinate function of discrete PKS proteins and the unusual glycosylation of an acyl carrier protein (ACP)-bound polyketide intermediate; 2) decipher the mode of formation of the ribomimetic core, which is predicted to take place via a distinctive biotransformation mediated by radical chemistry; and 3) develop and test new ribomimetic antibiotics for anti-infective activities. Successful completion of this research will advance scientific knowledge and technical capability in the field, and will address the current slow pace of progress in the discovery of new anti-infective drugs, particularly antibacterial, antiviral, and anti-parasitic agents.

项目概要糖模拟物长期以来因其重要的生物活性而闻名。其中许多目前都在使用在临床上作为抗菌药物（例如链霉素、庆大霉素、新霉素）、抗病毒药物（例如奥司他韦、帕拉米韦、恩替卡韦）和抗糖尿病药（例如阿卡波糖、伏格列波糖）。天然存在的糖模拟物包括氨基环戊醇，含有类似于核糖（核模拟物）的五元环醇单元。然而，由于其广谱毒性和/或产量低，尚未开发用于临床使用。因此，解决这些局限性可能会提供新的途径，以充分发挥其作为新产品的潜力。药物线索。该项目的长期目标是了解核糖模拟天然物质的生物合成产品并开发新的核糖模拟药物来对抗传染病。在本提案中，我们将重点研究含核糖拟肽的抗生素帕大霉素的生物合成和开发新的赤霉素类似物作为抗细菌、病毒和疟疾寄生虫的药物。我们的初步数据表明，帕大霉素核心结构的形成涉及极不寻常的离散聚酮合酶、广谱糖基转移酶和自由基 SAM 酶。我们还发现由于许多混杂的活性，帕大霉素的定制途径异常复杂。定制酶。此外，我们还开发了遗传、合成和化学酶策略（涉及广谱酮酰基-ACP 合酶 (KAS) III 样蛋白）生产新的 pactamycin 类似物和其他核模拟化合物，其中一些具有改善的生物特性。在此，我们建议：1）表征离散 PKS 蛋白的协调功能和酰基载体的异常糖基化蛋白质（ACP）结合的聚酮化合物中间体； 2）破译核糖拟核核心的形成模式，预计将通过自由基化学介导的独特生物转化发生； 3）开发和测试新的核糖模拟抗生素的抗感染活性。这项研究的成功完成将推动该领域的科学知识和技术能力，并将解决目前进展缓慢的问题新的抗感染药物的发现，特别是抗菌、抗病毒和抗寄生虫药物。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acarbose May Function as a Competitive Exclusion Agent for the Producing Bacteria.

阿卡波糖可作为生产细菌的竞争性排斥剂。

DOI：
发表时间：
2023-02-17
期刊：
影响因子：
4
作者：
Tanoeyadi, Samuel;Tsunoda, Takeshi;Ito, Takuya;Philmus, Benjamin;Mahmud, Taifo
通讯作者：
Mahmud, Taifo

Modifications of Protein-Bound Substrates by Trans-Acting Enzymes in Natural Products Biosynthesis.

天然产物生物合成中反式作用酶对蛋白质结合底物的修饰。

DOI：
发表时间：
2024-04-16
期刊：
影响因子：
0
作者：
Skala, Leigh E;Philmus, Benjamin;Mahmud, Taifo
通讯作者：
Mahmud, Taifo

Biosynthesis and Metabolic Engineering of Pseudo-oligosaccharides.

拟低聚糖的生物合成和代谢工程。

DOI：
10.1042/etls20180010
发表时间：
2018-08-30
期刊：
Emerging topics in life sciences
影响因子：
0
作者：
Abdullah R. Alanzi;Ananiya A Demessie;T. Mahmud
通讯作者：
T. Mahmud

Catalytic Mechanism of Nonglycosidic C-N Bond Formation by the Pseudoglycosyltransferase Enzyme VldE.

假糖基转移酶 VldE 形成非糖苷 C-N 键的催化机制。

DOI：
10.1021/acscatal.3c02404
发表时间：
2023-10-03
期刊：
ACS catalysis
影响因子：
12.9
作者：
Takeshi Tsunoda;Hatem A. Abuelizz;A. Samadi;Chin Piow Wong;T. Awakawa;Corey J. Brumsted;I. Abe;T. Mahmud
通讯作者：
T. Mahmud

Global and pathway-specific transcriptional regulations of pactamycin biosynthesis in Streptomyces pactum.

赤霉素链霉菌生物合成的全局和途径特异性转录调控。