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Combating Mult-Drug Resistant Bacteria

对抗多重耐药细菌

基本信息

批准号：
7390029
负责人：
Paul Hergenrother
金额：
$ 5.15万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-15 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7390029
关键词：
Active Sites Affinity Amino Acids Aminoglycoside Antibiotics Aminoglycosides Antibiotic Resistance Antibiotics Bacteria Bacterial Antibiotic Resistance Bacterial Drug Resistance Binding Binding Sites Biological Biological Assay Catalysis Cells Charge Class Classification Cloning Collection Communities DNA DNA Binding DNA biosynthesis Development Disruption Elements Enzymes Gene Mutation Genes Genus staphylococcus Health Hospitals Human In Vitro Infection Inherited Investigation Lead Libraries Life Macrolides Mass Spectrum Analysis Mediating Mediator of activation protein Messenger RNA Methicillin Resistance Modification Multi-Drug Resistance Nature Numbers Plasmids Positioning Attribute Property Proteins Public Health RNA RNA Binding Reaction Replication Initiation Reporter Genes Reporting Resistance Role Site Site-Directed Mutagenesis Stretching System Therapeutic Agents Time Tyrosine Vancomycin resistant enterococcus Vertebral column Work X-Ray Crystallography analog appendage bacterial resistance base beta-Lactams combinatorial concept design drug resistant bacteria ds-DNA enzyme activity enzyme mechanism in vivo inhibitor/antagonist inorganic phosphate novel strategies phosphoric diester hydrolase research study small molecule stem three dimensional structure tool

项目摘要

Bacterial resistance to antibiotics has emerged as a considerable threat to human health. Methicillin- resistant Staphloccous aureus (MRSA) and vancomycin-resistant enterococci (VRE) are multi-drug resistant bacteria that cause life threatening infections in the hospital setting and in some cases have leapt to the larger community. It is clear that new strategies and tactics are needed to combat these insidious bacteria. Often times, bacteria owe their antibiotic resistance to the proteins encoded by plasmids that they harbor. Plasmids are small, circular, extra-chromosomal pieces of DNA that can be transferred from one bacterium to another. These plasmids often contain genes that encode proteins that confer resistance to a wide array of antibiotics. Indeed, for several classes of antibiotics (including beta-lactams, macrolides, and aminoglycosides) plasmid-borne resistance is ubiquitous. In addition, many of the worst multi-drug resistant bacteria (including MRSA and VRE) are resistant by virtue of the plasmid they harbor. Proposed herein is a strategy to attack this plasmid-encoded resistance through the creation of "anti-plasmid" agents, small molecules that will vanquish the plasmid from the cell, thus rendering the bacteria sensitive to antibiotics. These compounds are designed to mimic a known, naturally occurring mechanism for plasmid elimination, known as plasmid incompatibility. The bio-molecules that determine plasmid incompatibility are typically small pieces of RNA and DNA iterons. It has been shown that genetic mutation of these RNA incompatibility determinants disrupts RNA loop-loop interactions and leads to plasmid elimination. In Specific Aims 1 and2 of this proposal, small molecules are described that will disrupt the RNA loop-loop interaction in a completely analogous manner, thus leading to plasmid elimination. Specific Aims 3 and 4 describe studies on the mechanism and inhibition of the plasmid replication initiation protein, RepA. The successful completion of the experiments described herein could lead to a dramatic change in the manner in which antibiotic resistant infections are treated.

细菌对抗生素的耐药性已成为对人类健康的巨大威胁。甲氧西林- 耐药金黄色葡萄球菌 (MRSA) 和耐药万古霉素肠球菌 (VRE) 具有多重耐药性在医院环境中引起危及生命的感染的细菌，在某些情况下已经传播到医院更大的社区。显然，需要新的战略和战术来对抗这些阴险的细菌。很多时候，细菌的抗生素耐药性归因于它们所携带的质粒编码的蛋白质。质粒是小的、环状的、染色体外的 DNA 片段，可以从一种细菌转移到另一个。这些质粒通常含有编码蛋白质的基因，这些蛋白质赋予多种抗性抗生素。事实上，对于几类抗生素（包括 β-内酰胺类、大环内酯类和氨基糖苷类药物）质粒传播的耐药性普遍存在。此外，许多最严重的多重耐药性细菌（包括 MRSA 和 VRE）因其携带的质粒而具有耐药性。本文提出的是通过创建“抗质粒”剂来攻击这种质粒编码的抗性的策略，小这些分子将从细胞中消灭质粒，从而使细菌对抗生素敏感。这些化合物旨在模拟已知的天然存在的质粒消除机制，称为质粒不相容性。决定质粒不相容性的生物分子通常是 RNA 和 DNA 迭代子的小片段。研究表明，这些RNA不相容性的基因突变决定簇破坏RNA环-环相互作用并导致质粒消除。具体目标 1 和 2 在该提案中，描述了小分子，它们将完全破坏 RNA 环-环相互作用。类似的方式，从而导致质粒消除。具体目标 3 和 4 描述了关于质粒复制起始蛋白 RepA 的机制和抑制。顺利完成本文描述的实验可能会导致抗生素耐药性的方式发生巨大变化感染得到治疗。