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：
10242726
负责人：
Christopher Akinleye Alabi
金额：
$ 23.17万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242726
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.

世界卫生组织将假单胞菌铜绿假单（铜绿假单胞菌）列为关键优先级1病原体疾病控制中心已将其列为“严重”的威胁水平，因为它已成为严重的住院和免疫受损的患者的威胁。铜绿假单胞菌是感染的常见原因包括肺炎，细菌，尿路感染和手术部位感染。耐药性在过去的十年中，致病生物已经显着增长，铜绿假单胞菌的感染构成了A 对公共卫生和国家安全的重大威胁。拟议的研究试图开发一个新的类 LECB靶向的卵子抗菌药物可以安全地清除由铜绿假单胞菌引起的感染。这研究工作直接解决了抗菌聚合物领域进展的关键障碍 - 减轻他们的全身毒性，其非特异性行动方式和改善生物膜穿透。为了解决困扰所有抗菌聚合物的关键选择性问题，包括新的序列定义的合成抗微生物寡素（寡素）实验室，我们提出了靶向大分子前药的合成，该前药积极针对假单胞菌仅在病毒存在下，铜绿菌（铜绿假单胞菌）并释放活性抗菌寡素铜绿假单胞菌发出的因素。这种作用机理，类似于抗体 - 药物领域的作用机理共轭物，应降低由于非特异性暴露而导致的毒性，同时保持效力感染部位的抗菌寡素。除了最大程度地减少毒性外，前药上的钉子还将还促进了生物膜穿透性，从而进一步改善了生物膜中寡聚的活性。这开发新类的抗菌化合物，这些化合物可以放射性多药耐药性铜绿假单胞菌将是巨大的好处，特别是对于住院和免疫受损的患者。这个影响鉴于当前加速抗生素抗性的时代，努力不能被夸大。