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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.

项目总结

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.