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: 8267916
• 负责人: David Elihu Greenberg
• 金额: $ 18.61万
• 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/8267916
• 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. PUBLIC HEALTH RELEVANCE: Multidrug resistance among Gram-negative bacterial pathogens is becoming increasingly frequent. We propose to utilize a novel anti-sense technology to rapidly develop and screen therapeutic compounds targeting essential genes as well as antibiotic resistance mechanisms in the multidrug resistant pathogens Escherichia coli and Acinetobacter baumannii. Because of the novelty of these antisense antibacterial compounds, they should be effective against bacteria that are resistant to existing antibiotics.

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，目前新型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，无毒”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和大肠杆菌。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，并抑制必需细菌基因的表达。 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（如氨苄青霉素）更有效。该项目的目标是开发用于治疗多重耐药病原体大肠杆菌和鲍曼不动杆菌的 PPMO。具体目标是针对多重耐药病原体大肠杆菌和鲍曼不动杆菌中的各种基因靶标设计、生产和筛选 PPMOS。实验方法是针对已知或怀疑对生物体生长至关重要的途径中的基因，包括脂多糖、肽聚糖和脂肪酸生物合成的基因。另一种方法是使用 PPMO 作为辅助疗法，针对特定的抗生素耐药机制，以恢复对目前使用的抗生素的敏感性。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。该项目将确定大肠杆菌和鲍曼不动杆菌中的主要目标 PPMO，并可将其推进临床前和临床研究。 公共卫生相关性：革兰氏阴性细菌病原体的多重耐药性正变得越来越频繁。我们建议利用一种新型反义技术来快速开发和筛选针对多重耐药病原体大肠杆菌和鲍曼不动杆菌中的必需基因以及抗生素耐药机制的治疗化合物。由于这些反义抗菌化合物的新颖性，它们应该能够有效对抗对现有抗生素产生耐药性的细菌。