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.

项目概要在抗击传染病方面，世界正迅速走向 1940 年代之前的情景疾病。抗生素耐药性是全球范围内日益严重的问题，极大地阻碍了我们的工作平息全球流行病（例如结核病和疟疾）的能力以及简单的方法葡萄球菌感染。拟议的项目意义重大，因为除非创新制定策略来生产强健有效的新型抗生素，医疗费用将继续攀升，我们将彻底失去战斗能力即使是最常见的感染。目前的抗生素治疗主要源自由真菌和细菌产生的天然产物，能够抑制其他微生物的生长生物体，通常通过抑制细胞壁合成或维持或通过抑制蛋白质合成。自 1929 年弗莱明首次分离出青霉素以来，随后的大多数几代抗生素仍然与原始天然产物非常相似，具有功能性修改后的群体可增加其对更广泛病原体的活性并减少他们的副作用概况。恶唑烷酮、糖肽、b-内酰胺和喹诺酮类药物显示出一些未来的希望，但革兰氏阴性细菌感染仍然是个问题。核酸是药物设计的有前途的途径，无论是作为治疗药物还是作为靶标。这里我们提出了一项创新计划来鉴定一类新型配体，这些配体是特异性针对 RNA 元件，该元件是抗生素耐药性的重要因素数十种致病细菌菌株，我们提出了一种生物物理筛选方法用于鉴定此类配体。首先，如具体目标 1 中所述，我们将描述一个模型已商业合成并经过修饰的核酸结构域该分子在本体溶液中的结构和动力学特性。然后我们将合成序列特异性 RNA 结合配体并筛选这些靶向缀合物库序列特异性结合并抑制靶核酸（具体目标 2）。一个成功应用该方法将使我们能够平息班级的抵抗途径广泛使用的抗生素——氨基糖苷类。