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Context-specific action of antibiotics targeting the catalytic center of the bacterial ribosome

针对细菌核糖体催化中心的抗生素的特定作用

基本信息

批准号：
9158354
负责人：
ALEXANDER S MANKIN
金额：
$ 39.98万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9158354
关键词：
Accounting Address Amino Acids Amino Acyl Transfer RNA Anti-Bacterial Agents Antibiotic Therapy Antibiotics Bacterial Infections Binding Binding Sites Biochemical C-terminal Catalytic Domain Cells Chloramphenicol Codon Nucleotides Data Development Drug effect disorder Drug usage Engineering Future Genes Genomics Goals Individual Initiator Codon Linezolid Location Medical Messenger RNA Molecular Nature Oxazolidinones Peptides Peptidyltransferase Pharmaceutical Preparations Play Property Protein Biosynthesis Protein Synthesis Inhibitors Proteins Proteome Resolution Ribosomes Role Site Specific qualifier value Specificity Structure Techniques Testing Translations base biophysical properties cell growth combat design genetic approach genome-wide analysis improved inhibitor/antagonist innovation insight novel therapeutics ribosome profiling single-molecule FRET treatment strategy

项目摘要

Antibiotics that inhibit cell growth by interfering with protein synthesis have been among the most clinically successful antibacterials. In spite of the importance of these inhibitors, there are significant gaps in our understanding of the most fundamental principles of their action. Many of the protein synthesis inhibitors, from the classic chloramphenicol (CHL) to the newer linezolid (LZD), bind at the catalytic peptidyl transferase center (PTC) of the ribosome, where they clash with the placement of aminoacyl-tRNA. Because of the location of their binding site, it is commonly assumed that they inhibit translation by interfering with formation of every peptide bond, either at the start codon or at any of the internal codons of a gene. However, our preliminary data show that this view is principally incorrect. Instead of indiscriminately inhibiting peptide bond formation, CHL and LZD stall elongation of translation only at specific mRNA sites. The nature of the nascent peptide chain appears to play the major role in specifying the sites of translation arrest, but the general rules that define the sites of stalling and the molecular mechanisms that underlie this effect remain unknown. Therefore, the main goal of this project is to gain a detailed understanding of the context specific action of PTC-targeting antibiotics. The study will primarily focus on LZD and CHL. LZD is the first and most broadly medically used oxazolidinone. CHL is one of the oldest known ribosomal antibiotics. In spite of its reduced medical importance, inclusion of CHL in the study is crucial, not only because of the vast amount of information available for this inhibitor, but also to contrast its context specific action with that of LZD and correlate the effects with individual structural properties of the drugs. In Specific Aim 1, whole-cell ribosome profiling and quantitative biochemical testing will be used to identify the detailed requirements for the sequence context that defines the preferred sites of inhibition of translation by LZD or CHL. In Specific Aim 2, an array of biochemical, structural and genetic approaches will be employed to understand the molecular mechanisms that account for the context-specific action of the PTC- targeting inhibitors. The use of innovative techniques, such as single molecule FRET or an engineered tethered ribosome, are expected to provide principally new insights into the most fundamental aspects of action of the inhibitors of the ribosomal catalytic center. Specific Aim 3 will address a conceptually important and medically-relevant question, whether context specificity of drug action results into protein-specific inhibition of translation by the PTC-targeting antibiotics. The anticipated findings should significantly expand the understanding of the general mode of action of clinically-important antibacterials that act upon the catalytic center of the ribosome and may open new venues for rational development of protein synthesis inhibitors with superior antibiotic properties.

通过干扰蛋白质合成来抑制细胞生长的抗生素是其中最多的