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A biophysical assay for RNA based resistance

基于 RNA 的耐药性的生物物理测定

基本信息

批准号：
10080557
负责人：
sandra Paige story
金额：
$ 28.89万
依托单位：
NUBAD, LLC
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：
2020-07-21 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080557
关键词：
Address Affinity Agar Amino Sugars Aminoglycoside Antibiotics Aminoglycoside resistance Aminoglycosides Antibiotic Resistance Antibiotic Therapy Antibiotic susceptibility Antibiotics Antimicrobial Resistance Antisense Oligonucleotides Awareness Bacteria Binding Biological Assay Biophysics Books Boston Cell Wall Chemicals Chemistry Communicable Diseases Congresses Development Diffusion Drug Design Drug Targeting Drug resistance Elements Enzymes Epidemic Fluorescence Future Generations Genes Genetic Glycopeptides Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Growth HIV Health Care Costs High Pressure Liquid Chromatography Hybrids Infection Institute of Medicine (U.S.)Isopropyl Thiogalactoside Lead Legal patent Letters Libraries Ligand Binding Ligands Maintenance Malaria MicroRNAs Modeling Modernization Modification Natural Products Nucleic Acids Organism Parasites Pathogenicity Pathway interactions Penicillins Pharmaceutical Preparations Phase Plasmids Positioning Attribute Property Protein Biosynthesis Quinolones RNA RNA Binding RNA Interference RNA Sequences Reporter Reporter Genes Resistance Ribosomes Solid Staphylococcal Infections Structure Surgeon Therapeutic Time Transferase Tuberculosis United States United States National Academy of Sciences Virus Work analog antibiotic resistant infections antimicrobial antimicrobial drug base beta-Lactamase beta-Lactams combat cost drug modification drug resistant pathogen experimental study fighting functional group fungus inhibitor/antagonist innovation interest microorganism novel pathogen pathogenic bacteria phosphorodiamidate morpholino oligomer promoter resistance gene restoration screening side effect targeted agent targeted delivery

项目摘要

PROJECT SUMMARY The world is rapidly heading towards a pre-1940's scenario when it comes to fighting infectious disease. Antimicrobial resistance is a growing problem on a global scale, greatly hampering our abilities to quell worldwide epidemics such as tuberculosis and malaria, as well as the simple staphylococcus infection. The proposed project is significant because unless innovative strategies are developed to produce robust and effective new classes of antibiotics, health care costs will continue to climb and we will completely lose our ability to combat even the most common infection. Current antibiotic treatments originated predominantly from natural products produced by fungi and bacteria that were able to inhibit the growth of other organisms, usually by inhibiting cell wall synthesis or maintenance or by inhibiting protein synthesis. Since penicillin was first isolated by Fleming in 1929, most of the subsequent generations of antibiotics remain very similar to the original natural products, with functional groups modified to increase their activity across a broader range of pathogens and decrease their side effect profiles. Oxazolidones, glycopeptides, b-lactams, and quinolones show some promise for the future, but gram-negative bacterial infections still remain problematic. Nucleic acids are promising avenues for drug design, both as therapeutics and as targets. Here we propose an innovative plan for identification of a novel class of ligands that are specific for an RNA element that is an important factor in the antibiotic resistance in dozens of pathogenic bacterial strains, and we propose a biophysical screening assay for identifying such ligands. First, as outlined in Specific Aim 1, we will characterize a model nucleic acid domain that has been synthesized commercially with modifications allowing structural and dynamic properties of this molecule in bulk solution. We will then synthesize sequence-specific RNA binding ligands and screen these targeted library of conjugates for sequence-specifically binding and inhibiting the target nucleic acid to (Specific Aim 2). A successful application of the approach will allow us to silence the resistance pathway for a class of widely used antibiotics-the aminoglycosides.

项目总结