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.

项目摘要长期以来，糖模拟物以其重要的生物学活动而闻名。其中许多目前已使用在诊所中，作为抗菌剂（例如链霉素，庆大霉素，新霉素），抗病毒药（例如Oseltamivir，Peramivir， Entecavir）和抗糖尿病（例如Acarbose，Voglibose）。在天然出现的糖模拟物中，有氨基拟南芥含有五元的环醇单元，类似于核糖（核糖素）。然而，由于它们的广谱毒性和/或生产率低，因此尚未开发用于临床用途。因此，解决这些局限毒品铅。该项目的长期目标是了解核糖质自然的生物合成产品并开发新的基于核糖核酸的药物来对抗传染病。在此提案中，我们将专注于询问含核糖核酸抗生素帕酸霉素的生物合成和作为药物，开发新的帕酸霉素类似物会导致细菌，病毒和疟疾寄生虫。我们的初步数据表明，帕乳毒素核心结构的形成涉及高度不寻常的离散聚酮化合物合酶，一种广谱糖基转移酶和一种自由基SAM酶。我们还发现由于许多混杂的活动调整酶。此外，我们开发了遗传，合成和化学酶策略（涉及宽光谱酮酰基-ACP合酶（KAS）III样蛋白）以产生新的帕塔梅霉素类似物和其他核糖成分，其中一些化合物改善了生物学特性。在这里，我们建议：1）表征离散PK蛋白的坐标功能和酰基载体的异常糖基化蛋白质（ACP） - 结合聚酮化合物中间体； 2）破译核糖核形成模式，该模式预计将通过自由基化学介导的独特生物转化进行。 3）发展和测试抗感染活动的新核糖局抗生素。成功完成这项研究将进步该领域的科学知识和技术能力，并将解决当前的进步速度缓慢发现新的抗感染药物，尤其是抗菌，抗病毒和抗寄生虫。

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）

The chemistry and biology of natural ribomimetics and related compounds.

DOI：
10.1039/d2cb00019a
发表时间：
2022-05-11
期刊：
RSC CHEMICAL BIOLOGY
影响因子：
4.1
作者：
Tsunoda, Takeshi;Tanoeyadi, Samuel;Proteau, Philip J.;Mahmud, Taifo
通讯作者：
Mahmud, Taifo

Identification and Biological Activity of NFAT-133 Congeners from Streptomyces pactum.

DOI：
10.1021/acs.jnatprod.1c00152
发表时间：
2021-09-24
期刊：
Journal of natural products
影响因子：
5.1
作者：
Zhou W;Posri P;Liu XJ;Ju Z;Lan WJ;Mahmud T
通讯作者：
Mahmud T

Functional Studies and Revision of the NFAT-133/TM-123 Biosynthetic Pathway in Streptomyces pactum.

DOI：
10.1021/acschembio.2c00454
发表时间：
2022-08-19
期刊：
ACS CHEMICAL BIOLOGY
影响因子：
4
作者：
Zhou, Wei;Alharbi, Hattan A.;Hummingbird, Eshe;Keatinge-Clay, Adrian T.;Mahmud, Taifo
通讯作者：
Mahmud, Taifo

EDB Gene Cluster-Dependent Indole Production Is Responsible for the Ability of Pseudomonas fluorescens NZI7 to Repel Grazing by Caenorhabditis elegans.