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: 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
• 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

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.

项目概要/摘要 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上升 增加导致全世界发病率和死亡率显着增加。此外，目前的管道 新抗菌药物的选择范围仍然非常狭窄。美国传染病学会在其研究中发现 “坏虫，无药”运动，一组对当前的耐药性越来越强的病原体 抗生素。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可以有效对抗多种抗生素。 细菌。这种新方法基于一种称为肽-磷酸二酰胺吗啉代的平台技术 低聚物（PPMO）。 PPMO 是合成的 DNA 模拟物，以序列特异性、反义的方式与 RNA 结合 方式并抑制必需细菌基因的表达。 PPMO 已成功用于杀灭 多种细菌病原体，包括革兰氏阴性菌、大肠杆菌、沙门氏菌 鼠伤寒杆菌、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， 减少菌血症并提高感染动物模型的存活率。 PPMO 比 许多传统抗生素，例如氨苄西林。该项目的目标是开发用于治疗的 PPMO 用于对抗多重耐药病原体大肠杆菌和鲍曼不动杆菌。具体的 目标是针对多重耐药性中的各种基因靶点设计、生产和筛选 PPMOS 病原体大肠杆菌和鲍曼不动杆菌。实验方法是针对以下途径中的基因 已知或怀疑对生物体的生长至关重要，包括生物合成的基因 脂多糖、肽聚糖和脂肪酸。另一种方法是使用 PPMO 作为辅助手段 疗法并针对特定的抗生素耐药机制，以恢复对目前的敏感性 用过抗生素。该技术提供了方法上的优势，因为许多 PPMO 可以快速 合成并同时针对众多目标进行测试。这允许定位的可能性 单一生物体中的多个基因或针对多种病原体的 PPMO 混合物的开发。 该项目将确定大肠杆菌和鲍曼不动杆菌中的主要目标 PPMO，这些目标可以推进到预研究阶段。 临床和临床研究。

项目成果

Peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) restores carbapenem susceptibility to NDM-1-positive pathogens in vitro and in vivo.

肽缀合的磷酸二酰胺吗啉寡聚物 (PPMO) 可在体外和体内恢复碳青霉烯类对 NDM-1 阳性病原体的敏感性。

• 发表时间: 2017
• 作者: Sully, Erin K;Geller, Bruce L;Li, Lixin;Moody, Christina M;Bailey, Stacey M;Moore, Amy L;Wong, Michael;Nordmann, Patrice;Daly, Seth M;Sturge, Carolyn R;Greenberg, David E
• 通讯作者: Greenberg, David E

Development of sequence-specific antimicrobials based on programmable CRISPR-Cas nucleases

基于可编程 CRISPR-Cas 核酸酶的序列特异性抗菌药物的开发

• DOI: 10.1021/acssuschemeng.7b00314
• 发表时间: 2024-09-13
• 期刊: ACS Sustainable Chemistry & Engineering
• 影响因子: 8.4
• 作者: David Bikard;Chad W. Euler;Wenyan Jiang;P. Nussenzweig;Gregory W. Goldberg;X. Duportet;V. Fischetti;L. Marraffini
• 通讯作者: L. Marraffini