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

• 批准号: 8463986
• 负责人: David Elihu Greenberg
• 金额: $ 16.77万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463986
• 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; antimicrobial; bacterial resistance; bactericide; base; beta-Lactam Resistance; design; fighting; improved; in vivo; killings; mortality; mouse model; novel; novel strategies; pathogen; phosphorodiamidate morpholino oligomer; pre-clinical; resistance mechanism; synthetic construct; therapeutic development; therapeutic target

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 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.

描述（由申请人提供）：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，导致全世界的发病率和死亡率很大。此外，当前的新抗菌药物管道仍然非常狭窄。美国传染病学会在其“坏虫子，无药物”运动中确定了一群对当前抗生素越来越抗药性的病原体。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，针对众多细菌有效显示了一种新的抗生素发现和设计范式。这种新方法基于一种称为肽磷酸缩补的平台技术，莫菲利诺基寡聚物（PPMO）。 PPMO是以序列特异性的反义方式与RNA结合的合成DNA模拟物，并抑制必需细菌基因的表达。 PPMO已成功用于杀死各种细菌病原体，包括革兰氏阴性细菌大肠杆菌，鼠伤寒沙门氏菌，伯克霍尔德cepacia complex综合体和鲍曼尼杆菌。 ppmos在培养中是杀菌性的，减少菌血症并改善感染动物模型的生存。 PPMO比许多传统的抗生素（例如氨苄青霉素）更有效。该项目的目的是开发PPMO，用于针对多药耐药病原体大肠杆菌和鲍曼尼杆菌的治疗用途。具体的目的是针对多种耐药病原体大肠杆菌和鲍曼尼I.的各种基因靶标设计，生产和筛选PPMO。实验方法是将已知或怀疑对于生长生长至关重要的途径中的靶向基因，包括脂多糖，肽聚糖和脂肪酸的生物合成基因。另一种方法是将PPMO用作辅助疗法和靶向特定的抗生素耐药性机制，以恢复对当前使用的抗生素的敏感性。该技术提供了方法论上的优势，因为许多PPMO可以快速合成并同时针对许多目标进行测试。这允许在单个生物体中靶向多个基因或靶向多种病原体的PPMO鸡尾酒的发展。该项目将确定大肠杆菌和鲍曼尼曲霉中的铅靶PPMO，可以将其前进到临床前和临床研究。