Circumventing Antibiotic Resistance with Novel Gene-Silencing Therapeutics

用新型基因沉默疗法规避抗生素耐药性

基本信息

批准号：
9223787
负责人：
BRUCE L GELLER
金额：
$ 47.48万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9223787
关键词：
Acinetobacter Acinetobacter baumannii Americas Ampicillin Animal Model Animals Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antisense Technology Bacteremia Bacteria Bacterial Genes Binding Biological Assay Burkholderia cepacia complex Cell physiology Clinical Clinical Research Communicable Diseases Conserved Sequence Databases Development Escherichia coli Essential Genes Future Gene Silencing Gene Targeting Genes Goals Gram-Negative Bacteria Growth Health Human In Vitro Infection Inflammation Klebsiella Klebsiella pneumonia bacterium Lead Lung Microbial Biofilms Morbidity - disease rate Multi-Drug Resistance Organism Outcome Pathway interactions Peptides Pharmaceutical Preparations Phase Predisposition Property Pseudomonas Pseudomonas aeruginosa Publishing RNA Resistance Resistance development Ribosomal RNA Salmonella typhimurium Societies Technology Testing Therapeutic Therapeutic Uses Translations Virulence antimicrobial bacterial resistance bactericide base design efficacy testing fighting improved in vivo killings mortality mouse model multi-drug resistant pathogen novel novel strategies novel therapeutics pathogen phosphorodiamidate morpholino oligomer pre-clinical pressure resistance gene resistance mechanism screening synthetic construct therapeutic development therapeutic target

项目摘要

DESCRIPTION (provided by applicant): 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, Pseudomonas aeruginosa and Klebsiella pneumoniae. 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 target 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 Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. The specific aims are to design, produce and screen PPMOS against various gene targets in these multidrug-resistant pathogens. The experimental approach will be to target virulence properties in Acinetobacter and Pseudomonas, and essential or antibiotic resistance genes in Klebsiella. Lead compounds that are effective during our screening phase will then be tested for efficacy in animal models of infection. 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 these medically important Gram- negative pathogens that can be moved forward to pre-clinical and clinical studies.

描述（由申请人提供）：对新型抗菌药物的需求日益迫切。多重耐药病原体的比率持续增加，导致全世界的发病率和死亡率显着增加。此外，目前新抗菌药物的研发管线仍然非常狭窄。美国传染病学会在其“坏虫，无药”运动中发现了一组对当前抗生素的耐药性越来越强的病原体。该组包括革兰氏阴性病原体鲍曼不动杆菌、铜绿假单胞菌和肺炎克雷伯菌。最近，抗生素发现和设计的新范例已被证明对多种细菌有效。这种新方法基于一种称为肽-磷酸二酰胺吗啉低聚物 (PPMO) 的平台技术。 PPMO 是合成的 DNA 模拟物，以序列特异性、反义方式与 RNA 结合并抑制目标细菌基因的表达。 PPMO 已成功用于杀死多种细菌病原体，包括革兰氏阴性菌、大肠杆菌、鼠伤寒沙门氏菌、洋葱伯克霍尔德菌复合体和鲍曼不动杆菌。 PPMOS 在培养物中具有杀菌作用，可减少感染动物模型中的菌血症并提高存活率。 PPMO 比许多传统抗生素（如氨苄西林）更有效。该项目的目标是开发用于治疗多重耐药病原体鲍曼不动杆菌、铜绿假单胞菌和肺炎克雷伯菌的 PPMO。具体目标是针对这些多重耐药病原体中的各种基因靶标设计、生产和筛选 PPMOS。实验方法将针对不动杆菌和假单胞菌的毒力特性，以及克雷伯氏菌的必需基因或抗生素抗性基因。在我们的筛选阶段有效的先导化合物将在动物感染模型中进行功效测试。该技术具有方法学优势，因为可以快速合成许多 PPMO，并同时针对众多目标进行测试。这使得有可能针对单个生物体中的多个基因或开发针对多种病原体的 PPMO 混合物。该项目将确定这些医学上重要的革兰氏阴性病原体中的主要靶标 PPMO，并可将其推进临床前和临床研究。