Novel gene-silencing therapeutics for multidrug-resistant gram-negative pathogens

针对多重耐药革兰氏阴性病原体的新型基因沉默疗法

基本信息

批准号：
9055626
负责人：
David Elihu Greenberg
金额：
$ 35.97万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9055626
关键词：
Acinetobacter baumannii Algorithms Americas Ampicillin Animal Model Animals Anti-Bacterial Agents Antibiotic Resistance Antibiotic-resistant organism Antibiotics Bacteremia Bacteria Bacterial Genes Binding Burkholderia cepacia complex Clinical Clinical Research Communicable Diseases Databases Development Escherichia coli Essential Genes Fatty Acids Future Gene Silencing Gene Targeting Genes Goals Gram-Negative Bacteria Growth Hospitals Human In Vitro Infection Inflammation Lead Lipopolysaccharide Biosynthesis Pathway Minimum Inhibitory Concentration measurement Morbidity - disease rate Multi-Drug Resistance Mus Organism Pathway interactions Peptides Peptidoglycan Pharmaceutical Preparations Phase Predisposition RNA Resistance Role Salmonella Salmonella typhimurium Societies Technology Testing Therapeutic Therapeutic Agents Therapeutic Uses abstracting antimicrobial bacterial resistance bactericide base beta-Lactam Resistance design fighting improved in vivo killings mortality mouse model multi-drug resistant pathogen novel novel strategies pathogen phosphorodiamidate morpholino oligomer pre-clinical resistance gene resistance mechanism synthetic construct targeted treatment therapeutic development therapeutic target

项目摘要

Project Summary/Abstract The need for new antimicrobials is increasingly urgent. The rate of multidrug resistant pathogens continues to increase leading to significant morbidity and mortality throughout the world. Furthermore, the current pipeline for new antimicrobials remains very narrow. The Infectious Diseases Society of America has identified in their "Bad Bugs, No Drugs" campaign, a group of pathogens that have become increasingly resistant to current antibiotics. This group includes the Gram-negative pathogens Acinetobacter baumannii and Escherichia coli. A new paradigm in antibiotic discovery and design has recently been shown effective against numerous bacteria. This new approach is based on a platform technology called peptide-phosphorodiamidate mopholino oligomers (PPMOs). PPMOs are synthetic DNA mimics that bind to RNA in a sequence-specific, antisense manner and inhibit expression of essential bacterial genes. PPMOs have already been used successfully to kill a variety of bacterial pathogens including the Gram-negative bacteria Escherichia coli, Salmonella typhimurium, Burkholderia cepacia complex and Acinetobacter baumannii. PPMOS are bactericidal in culture, and reduce bacteremia and improve survival in animal models of infection. PPMOs are more potent than many traditional antibiotics such as ampicillin. The goal of this project is to develop PPMOs for therapeutic use against the multidrug resistant pathogens Escherichia coli and Acinetobacter baumannii. The specific aims are to design, produce and screen PPMOS against various gene targets in the multidrug-resistant pathogens E. coli and A. baumannii. The experimental approach is to target genes in pathways that are known or suspected to be essential for the growth of the organism, including genes for biosynthesis of lipopolysaccharide, peptidoglycan, and fatty acids. Another approach will be to use PPMOs as adjunctive therapies and target specific antibiotic resistance mechanisms in order to restore susceptibility to currently used antibiotics. This technology provides a methodological advantage because many PPMOs can be rapidly synthesized and simultaneously tested against numerous targets. This allows for the possibility of targeting multiple genes in a single organism or the development of cocktails of PPMOs that target multiple pathogens. This project will identify lead target PPMOs in E. coli and A. baumannii that can be moved forward to pre- clinical and clinical studies.

项目摘要/摘要新抗菌剂的需求越来越紧迫。多药耐药病原体的速度继续增加导致全世界的大量发病和死亡率。此外，当前管道对于新的抗微生物，仍然非常狭窄。美国传染病学会已经确定 “坏虫子，没有毒品”运动，这是一群对当前越来越抗药性的病原体抗生素。该组包括革兰氏阴性病原体鲍曼尼（Baumannii）和大肠杆菌（Escherichia Coli）。最近显示出一种新的抗生素发现和设计范式，可对众多细菌。这种新方法基于一种称为肽 - 磷酸缩影的平台技术低聚物（ppmos）。 PPMO是合成DNA模拟物，以序列特异性，反义结合RNA 方式并抑制必需细菌基因的表达。 ppmos已经成功地用于杀死多种细菌病原体，包括革兰氏阴性细菌大肠杆菌，沙门氏菌 Typhimurium，Burkholderia cepacia Complex和Acinetobacter Baumannii。 ppmos在培养中是杀菌性的，并减少菌血症并改善感染动物模型的生存。 ppmos比许多传统的抗生素，例如氨苄青霉素。该项目的目的是开发用于治疗的PPMO 使用抗多药的病原体大肠杆菌和鲍曼尼杆菌。具体目的是针对耐多种基因靶标设计，生产和屏幕ppmos 病原体大肠杆菌和A. baumannii。实验方法是靶向基因已知或怀疑对于生物的生长至关重要，包括用于生物合成的基因脂多糖，肽聚糖和脂肪酸。另一种方法是将PPMO用作辅助手段疗法和靶向特定的抗生素抗性机制，以恢复当前的敏感性使用的抗生素。该技术提供了方法论上的优势，因为许多PPMO可以迅速对许多目标进行了合成和同时测试。这允许定位单个生物体中的多个基因或针对多种病原体的PPMO鸡尾酒的发展。该项目将确定大肠杆菌和鲍曼尼a。临床和临床研究。