权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeted Macromolecular Antimicrobial Prodrugs Against Pseudomonas Aeruginosa

针对铜绿假单胞菌的靶向大分子抗菌前药

基本信息

批准号：
10042971
负责人：
Christopher Akinleye Alabi
金额：
$ 18.92万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10042971
关键词：
Address Affinity Anti-Bacterial Agents Antibiotic Resistance Antibody-drug conjugates Attenuated Bacteremia Bacteria Binding Cations Cell Death Cell membrane Cells Centers for Disease Control and Prevention (U.S.)Charge Cholesterol Cleaved cell Cystic Fibrosis Development Disease Drug resistance Enzymes Goals Gram-Negative Bacteria Hand Host Defense Hydrophobicity Immune In Vitro Infection Intravenous Kinetics Laboratories Lectin Lipids Mammalian Cell Maximum Tolerated Dose Mediating Membrane Microbial Biofilms Modeling Molecular Weight Mucous Membrane Multi-Drug Resistance National Security Organism Pathogenicity Patients Penetration Peptide Hydrolases Peptides Pneumonia Polymers Predisposition Prodrugs Pseudomonas Pseudomonas aeruginosa Public Health Research Resistance Route Serum Serum Proteins Site Sodium Chloride Specificity Surface Surgical Wound Infection Testing Time Toxic effect United States National Institutes of Health Urinary tract infection Vertebral column Virulence Factors World Health Organization amphiphilicity antimicrobial antimicrobial peptide burn wound chronic wound clinical translation design glycyl-glycyl-glycine hydrophilicity improved in vitro activity in vivo interest macromolecule multidrug-resistant Pseudomonas aeruginosa nanomolar pathogen protein aminoacid sequence quorum sensing research study residence systemic toxicity targeted agent

项目摘要

The World Health Organization lists Pseudomonas aeruginosa (P. aeruginosa) as a critical priority 1 pathogen and the Center for Disease Control has it listed at a threat level of “serious” because it has become a severe threat for hospitalized and immune-compromised patients. P. aeruginosa is a common cause of infections including pneumonia, bacteremia, urinary tract infections, and surgical site infections. Drug resistance in this pathogenic organism has grown significantly in the last decade and infections with P. aeruginosa pose a significant threat to public health and national security. The proposed research seeks to develop a new class of LecB targeted PEGylated antimicrobial prodrugs that can safely clear infections caused by P. aeruginosa. This research effort directly addresses a critical barrier to progress in the field of antimicrobial polymers – mitigating their systemic toxicity brought about by their non-specific mode of action and improving their biofilm penetration. To address this critical selectivity problem that plagues all antimicrobial polymers, including new sequence-defined synthetic antimicrobial oligothioetheramides (oligoTEAs) made in our laboratory, we propose the synthesis of targeted macromolecular prodrugs that actively target Pseudomonas aeruginosa (P. aeruginosa) and release the active antimicrobial oligoTEA only in the presence of virulence factors emitted by P. aeruginosa. This mechanism of action, similar to that used in the field of antibody-drug conjugates, should decrease toxicity due to non-specific exposure while maintaining the potency of the antimicrobial oligoTEA at the site of infection. In addition to minimizing toxicity, the PEG on the prodrug will also facilitate biofilm penetration thus further improving activity of the oligoTEAs in a biofilm. The development of new classes of antibacterial compounds that can eradicate multi-drug resistant P. aeruginosa will be of immense benefit, particularly for hospitalized and immune-compromised patients. The impact of this effort cannot be overstated given the current era of accelerated antibiotic resistance.

世界卫生组织将铜绿假单胞菌（P. aeruginosa）列为关键优先级1病原体疾病控制中心将其列为“严重”威胁级别，因为它已经成为一种严重的对住院和免疫力低下的患者构成威胁。铜绿假单胞菌是感染的常见原因包括肺炎、菌血症、尿路感染和手术部位感染。耐药性在这病原微生物在过去十年中显著增长，铜绿假单胞菌感染构成了一种新的病原微生物。对公共卫生和国家安全构成重大威胁。拟议的研究旨在开发一类新的 LecB靶向聚乙二醇化抗微生物前药，可安全清除铜绿假单胞菌引起的感染。这研究工作直接解决了抗微生物聚合物领域进展的关键障碍- 减轻由其非特异性作用模式引起的全身毒性，并改善其生物膜渗透为了解决困扰所有抗菌聚合物的这个关键选择性问题，包括新的序列定义的合成抗菌低聚硫醚酰胺（oligoTEA），在实验室，我们提出了合成靶向大分子前药，积极靶向假单胞菌铜绿假单胞菌（P. aeruginosa），仅在毒力存在时释放活性抗微生物oligoTEA 铜绿假单胞菌释放的因子。这种作用机制类似于抗体药物领域中使用的作用机制。偶联物，应降低由于非特异性暴露的毒性，同时保持偶联物的效力。在感染部位使用抗微生物oligoTEA。除了使毒性最小化之外，前药上的PEG将还促进生物膜渗透，从而进一步提高生物膜中寡TEA的活性。的开发新型抗菌化合物，可根除多重耐药铜绿假单胞菌将有巨大的好处，特别是对住院和免疫功能低下的患者。这样做的影响考虑到当前抗生素耐药性加速的时代，努力不能被夸大。