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Biosynthesis of nucleoside antibiotics targeting bacterial translocase I

针对细菌易位酶 I 的核苷抗生素的生物合成

基本信息

批准号：
9903243
负责人：
Steven Gary Van Lanen
金额：
$ 37.31万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903243
关键词：
AIDS/HIV problem Aldehydes Amides Anabolism Anti-Bacterial Agents Antibiotics Bacteria Cell Wall Cessation of life Chemicals Clinic Clinical Data Decarboxylation Development Dioxygenases Disease Drug resistance Drug resistance in tuberculosis Enzymes Fatty Acids Genetic Engineering Genome Genomics Goals Health Hospitals Human In Vitro Lead Logic Methodology Mining Modality Molecular Multiple Bacterial Drug Resistance Mus Natural Product Drug Nucleosides Oxidoreductase Pathway interactions Peptides Peptidoglycan Pharmaceutical Preparations Phosphotransferases Process Proteins Public Health Pyridoxal Phosphate Research S-Adenosylmethionine Scanning Side Staphylococcus aureus infection Streptomyces Structure System Time Toxic effect Transaldolase Transketolase Tuberculosis United States Uridine Uridine Monophosphate World Health Organization alpha ketoglutarate analog clinical application community setting drug discovery enzyme pathway expectation improved in vivo in vivo Model inhibitor/antagonist member methicillin resistant Staphylococcus aureus multi-drug resistant pathogen nanomolar novel nucleophilic substitution pathogen piperidine prevent scaffold synthetic biology tool translocase

项目摘要

New antibiotics are needed, particularly those that can be considered as new chemical entities and have novel targets relative to the current, clinical armament of antibiotics. Highly modified nucleoside antibiotics that inhibit bacterial translocase I (TL1) involved in cell wall biosynthesis fit both these descriptions, and have excellent potential in part because they are (i) nanomolar inhibitors of TL1, (ii) inhibit a target that has been proven to be essential for the survival of most, if not all, bacteria, (iii) are effective antibiotics in both in vitro and in vivo models, and (iv) have no apparent toxicity in mice. We have defined the biosynthetic mechanism leading to the core disaccharyl-nucleoside structure of several promising nucleoside antibiotics including A-90289 from Streptomyces sp. SANK 60405, muraminomicin from Streptosporangium sp, and muraymycin from Streptomyces sp. LL-AA896 using a combined in vivo and in vitro approach. The results have defined a multi-enzyme pathway highlighted by divergence from the primary building block UMP and reconvergence to form the core nucleoside. This data was utilized to scan the wealth of genomic information to identify a new lead antibiotic, sphaerimicin, which was isolated and revealed to share the nucleoside core structure but have several unique features including a dihydroxylated piperidine ring of unknown origin. We will now accomplish the following specific aims: (i) to define the mechanism for the attachment of the 3-amino-3-carboxypropyl (3A3CP) moiety that generates the last, shared intermediate in the biosynthesis of A-90289, muraminomicin, muraymycin, and sphaerimicin, which is hypothesized to occur via a new enzyme strategy catalyzed by a pyridoxal-5′-phosphate-dependent protein and (ii) to delineate the biosynthetic mechanism for divergence from the last, shared intermediate to generate unique, nucleoside core scaffolds that are further decorated by fatty acids, polyketides, nonribosomal peptides, and/or saccharides. A biosynthetic mechanism for the diazepanone ring for A-90289 and the highly unusual fused piperidine ring system in sphaerimicin will be defined.

需要新的抗生素，特别是那些可以被视为新化学实体的抗生素并且相对于当前的临床抗生素武器具有新的靶点。高度修饰抑制参与细胞壁生物合成的细菌移位酶I（TL 1）的核苷类抗生素这两种描述，并有很好的潜力，部分是因为他们是（i）纳摩尔 TL 1的抑制剂，（ii）抑制已被证明对大多数人的生存至关重要的靶标，如果不是全部，细菌，（iii）在体外和体内模型中都是有效的抗生素，和（iv）没有小鼠明显毒性。我们已经确定了导致核心的生物合成机制包括A-90289在内的几种有前途的核苷类抗生素的二乙酰核苷结构来自链霉菌属SANK 60405的胞壁霉素，使用组合的体内和体外方法从链霉菌属LL-AA 896中获得Muraymycin。这些结果已经定义了一个多酶途径，突出显示了与主要酶的分歧。构建块UMP和再会聚以形成核心核苷。这些数据用于扫描丰富的基因组信息，以确定一种新的领先抗生素，球孢菌素，这是分离并显示共享核苷核心结构，但具有几个独特的特征包括来源不明的二羟基化哌啶环。我们现在将完成以下工作具体目的：（i）确定3-氨基-3-羧基丙基的连接机制，（3A 3CP）部分，其在A-90289的生物合成中产生最后的共享中间体， Muraminomicin、Muraymycin和sphaerimicin，假设其通过一种新的酶发生策略催化的吡哆醛-5 ′-磷酸依赖性蛋白质和（ii）描绘生物合成机制的分歧，从最后，共享中间产生独特的，核苷核心支架进一步被脂肪酸、聚酮化合物、非核糖体肽和/或肽。A-90289二氮杂环庚烷酮环的生物合成机理并定义了球孢霉素中高度不寻常的稠合哌啶环系统。

项目成果

期刊论文数量（13）

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 Role of a Nonribosomal Peptide Synthetase in l-Lysine Lactamization During Capuramycin Biosynthesis.

DOI：
10.1002/cbic.201500701
发表时间：
2016-05-03
期刊：
Chembiochem : a European journal of chemical biology
影响因子：
0
作者：
Liu X;Jin Y;Cui Z;Nonaka K;Baba S;Funabashi M;Yang Z;Van Lanen SG
通讯作者：
Van Lanen SG

Amalgamation of nucleosides and amino acids in antibiotic biosynthesis: discovery of an L-threonine:uridine-5'-aldehyde transaldolase.

DOI：
10.1021/ja308185q
发表时间：
2012-11-14
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Barnard-Britson, Sandra;Chi, Xiuling;Nonaka, Koichi;Spork, Anatol P.;Tibrewal, Nidhi;Goswami, Anwesha;Pahari, Pallab;Ducho, Christian;Rohr, Jurgen;Van Lanen, Steven G.
通讯作者：
Van Lanen, Steven G.

Structure-based gene targeting discovery of sphaerimicin, a bacterial translocase I inhibitor.

DOI：
10.1002/anie.201305546
发表时间：
2013-10-25
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
影响因子：
16.6
作者：
Funabashi, Masanori;Baba, Satoshi;Takatsu, Toshio;Kizuka, Masaaki;Ohata, Yasuo;Tanaka, Masahiro;Nonaka, Koichi;Spork, Anatol P.;Ducho, Christian;Chen, Wei-Chen Leyla;Van Lanen, Steven G.
通讯作者：
Van Lanen, Steven G.

Fe(II)-dependent, uridine-5'-monophosphate α-ketoglutarate dioxygenases in the synthesis of 5'-modified nucleosides.

Fe(II) 依赖性、尿苷-5-单磷酸α-酮戊二酸双加氧酶参与 5-修饰核苷的合成。