Novel therapeutic approaches for treatment of drug-resistant Gram-positive infections

治疗耐药革兰氏阳性菌感染的新方法

基本信息

批准号：
10301362
负责人：
Konstantin V Korotkov
金额：
$ 7.65万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2020-11-12 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10301362
关键词：
Acinetobacter baumannii Affinity Alpaca Anabolism Animals Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antibodies Bacteria Bacterial Infections Bacterial Physiology Binding Biogenesis Biological Camels Cell Wall Cell division Cell membrane Cell physiology Cells Complex Core Protein Data Development Drug Controls Drug Targeting Drug resistance ESKAPE pathogens Enterobacter Enterococcus Enterococcus faecalis Enterococcus faecium Enzymes Extracellular Domain Future Genetic study Genus staphylococcus Glycerol Goals Gram-Positive Bacteria Gram-Positive Bacterial Infections Growth Healthcare Systems Hospitals Immune Evasion Immunization Immunize Immunoglobulin Fragments In Vitro Infection Ions Kentucky Klebsiella pneumoniae Libraries Link Llama Measures Medical Methicillin Resistance Modeling Modification Outcomes Research Pathogenicity Pathway interactions Peptidoglycan Permeability Phage Display Pharmaceutical Preparations Phosphatidylglycerols Play Polysaccharides Problem Solving Process Property Proteins Pseudomonas aeruginosa Publishing Resistance development Role Specificity Staphylococcus aureus Staphylococcus aureus infection Teichoic Acids Testing Thick Transferase Tunicamycin Universities Vancomycin Resistance Vertebral column Virulence antigen binding antimicrobial peptide cell envelope cold temperature design drug resistant bacteria experience experimental study human pathogen in vivo inorganic phosphate insight lipoteichoic acid member methicillin resistant Staphylococcus aureus nanobodies novel novel therapeutic intervention novel therapeutics pathogen pathogenic bacteria targeted agent targeted treatment

项目摘要

Emergence of hospital-associated drug-resistant bacterial infections represents one of the major challenges for the US healthcare system. There is an urgent need for development of new and more effective anti-bacterial agents targeting previously unexplored cellular processes. The goal of this proposal is to find a novel class of biological drugs active against Staphylococcus aureus and pathogenic Enterococci. The bacterial cell wall biogenesis is an established drug target for many existing and novel antibacterial agents. In recent years, lipoteichoic acid biosynthesis pathways emerged as an attractive target for development of new therapeutics. Published data indicate that lipoteichoic acid is required for the growth and survival of Gram-positive bacteria in the host. The experiments in this proposal are designed to generate single domain camelid antibodies (nanobodies) that bind and inactivate extracellular domains of enzymes involved in synthesis and modification of lipoteichoic acid. Upon successful completion of this project we will obtain a number of nanobodies active against S. aureus and Enterococci that would be further validated in in vivo studies. The strategies developed in the proposed study will be also applicable to other medically relevant bacterial pathogens.

医院相关耐药细菌感染的出现代表了其中之一美国医疗保健系统面临的主要挑战。迫切需要开发新的、更有效的针对先前的抗菌剂未探索的细胞过程。该提案的目标是找到一类新颖的对金黄色葡萄球菌和致病性肠球菌具有活性的生物药物。这细菌细胞壁生物合成是许多现有和新型药物的既定药物靶点抗菌剂。近年来，脂磷壁酸生物合成途径出现作为开发新疗法的有吸引力的目标。公布的数据表明脂磷壁酸是革兰氏阳性菌生长和存活所必需的主持人。本提案中的实验旨在生成单域骆驼科动物结合酶胞外域并使其失活的抗体（纳米抗体）参与脂磷壁酸的合成和修饰。成功完成后在这个项目中，我们将获得许多具有抗金黄色葡萄球菌活性的纳米抗体，肠球菌将在体内研究中得到进一步验证。制定的战略拟议的研究也适用于其他医学相关细菌病原体。