A biophysical assay targeting Gyrase RNA

针对旋转酶 RNA 的生物物理测定

基本信息

批准号：
10480107
负责人：
sandra Paige story
金额：
$ 29.45万
依托单位：
NUBAD, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-11 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10480107
关键词：
Abdominal Infection Address Affinity Amino Sugars Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Antisense Oligonucleotides Awareness Bacillus Bacteria Bacterial Antibiotic Resistance Bacterial Infections Base Sequence Binding Biological Assay Biophysics Boston Cell Wall Cell membrane Cells Cessation of life Chemistry Clinical Code Colistin Communicable Diseases DNA DNA Gyrase DNA biosynthesis Data Development Drug Design Drug resistance Enterobacteriaceae Enzymes Epidemic Escherichia coli Essential Genes Family Fluorescence Future Gene Targeting Generations Genes Genetic Recombination Genetic Transcription Glycopeptides Gram-Negative Bacteria Gram-Negative Bacterial Infections Growth HIV Health Care Costs High Pressure Liquid Chromatography Hybrids Infection Institute of Medicine (U.S.)Intra-abdominal Klebsiella Lactams Lead Legal patent Length Length of Stay Libraries Ligand Binding Ligands Maintenance Malaria Messenger RNA MicroRNAs Microbial Drug Resistance Modeling Morbidity - disease rate Multi-Drug Resistance Natural Products Nosocomial Infections Nucleic Acid Binding Nucleic Acids Organism Parasites Pathogenicity Penicillins Peptide Nucleic Acids Peptides Persons Pharmaceutical Preparations Phase Play Pneumonia Protein Biosynthesis Quinolones RNA RNA Binding RNA Interference RNA Sequences RNA chemical synthesis Rapid screening Reporter Reporter Genes Resistance Resistance profile Ribosomes Salmonella Sepsis Severities Shigella Solid Staphylococcal Infections Structure System Therapeutic Topoisomerase II Toxic effect Translations Tuberculosis United States United States National Academy of Sciences Urinary tract infection Virus Wit Work World Health Organization alternative treatment analog antibiotic resistant infections antimicrobial antimicrobial drug base carbapenem-resistant Enterobacteriaceae combat cost economic impact experimental study extensive drug resistance fighting functional group fungus immunogenic improved innovation interest member microorganism mortality novel novel antibiotic class novel strategies novel therapeutics off-target site pathogen phase 2 study priority pathogen screening side effect targeted agent targeted delivery tigecycline uptake

Abdominal Infection Address Affinity Amino Sugars Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Antisense Oligonucleotides Awareness Bacillus Bacteria Bacterial Antibiotic Resistance Bacterial Infections Base Sequence Binding Biological Assay Biophysics Boston Cell Wall Cell membrane Cells Cessation of life Chemistry Clinical Code Colistin Communicable Diseases DNA DNA Gyrase DNA biosynthesis Data Development Drug Design Drug resistance Enterobacteriaceae Enzymes Epidemic Escherichia coli Essential Genes Family Fluorescence Future Gene Targeting Generations Genes Genetic Recombination Genetic Transcription Glycopeptides Gram-Negative Bacteria Gram-Negative Bacterial Infections Growth HIV Health Care Costs High Pressure Liquid Chromatography Hybrids Infection Institute of Medicine (U.S.)Intra-abdominal Klebsiella Lactams Lead Legal patent Length Length of Stay Libraries Ligand Binding Ligands Maintenance Malaria Messenger RNA MicroRNAs Microbial Drug Resistance Modeling Morbidity - disease rate Multi-Drug Resistance Natural Products Nosocomial Infections Nucleic Acid Binding Nucleic Acids Organism Parasites Pathogenicity Penicillins Peptide Nucleic Acids Peptides Persons Pharmaceutical Preparations Phase Play Pneumonia Protein Biosynthesis Quinolones RNA RNA Binding RNA Interference RNA Sequences RNA chemical synthesis Rapid screening Reporter Reporter Genes Resistance Resistance profile Ribosomes Salmonella Sepsis Severities Shigella Solid Staphylococcal Infections Structure System Therapeutic Topoisomerase II Toxic effect Translations Tuberculosis United States United States National Academy of Sciences Urinary tract infection Virus Wit Work World Health Organization alternative treatment analog antibiotic resistant infections antimicrobial antimicrobial drug base carbapenem-resistant Enterobacteriaceae combat cost economic impact experimental study extensive drug resistance fighting functional group fungus immunogenic improved innovation interest member microorganism mortality novel novel antibiotic class novel strategies novel therapeutics off-target site pathogen phase 2 study priority pathogen screening side effect targeted agent targeted delivery tigecycline uptake

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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, wit h functional groups modified to increase their activity across a broader range of pathogens and decrease their side effect profiles. Oxazolidones, glycopeptides, -lactams, and quinolones show some promise for the future, but Gram-negative bacterial infections still remain problematic. Cases of multidrug-resistant (MDR, resistance to 2-3 classes), extensive drug resistance (XDR, resistance to most classes except colistin or tigecycline) and even pan drug resistance (PDR, resistance to all classes) nosocomial bacterial infections have skyrocketed in recent years, and the emergence of pan drug-resistant isolates are making these infections increasingly difficult to treat. Hospital-acquired infections like these account for up to 4% of all hospital stays in the United States and are incredibly diverse in causative pathogen, antibiotic resistance profile, and severity. A significant cause of nosocomial infection is the Enterobacteriaceae family, which includes Gram-negative bacilli that can be commensal or pathogenic. Enterobacteriaceae have a widespread clinical and economic impact due to the diversity of infections they cause; this family causes many infections such as pneumonia, bloodstream infections (BSIs), urinary tract infections (UTIs), and intra- abdominal infections (IAIs). The World Health Organization (WHO) lists carbapenem-resistant Enterobacteriaceae (CRE) as having a critical need for novel antibiotics on their Priority Pathogens list. Because the mortality of these multi drug-resistant infections is between 30 and 50% and there is such difficulty in finding viable treatments, the need for novel therapeutics for these pathogens must be addressed. Nucleic acids are promising avenues for drug design, both as therapeutics and as targets. Targeting heavily conserved RNA sequences and structures, in bacteria (Enterobacteriaceae), and involved in proliferation and survival of bacteria, is a promising approach. Using our proprietary probes, assays and libraries, we propose to develop a screening assay for an essential gene in Enterobacteriaceae. Here we propose an innovative plan for identification of a novel class of ligands that are specific for an mRNA present in an essential gene in bacteria, 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 will be synthesized commercially and identify specific and high-affinity aminosugar binders. We will then synthesize sequence-specific RNA binding ligands and screen this targeted library of conjugates for sequence-specific binding and gene inhibition. The mechanism of action will be confirmed using a reporter gene assay (Specific Aim 2). A successful application of the approach will allow us to identify and validate lead compounds for inhibition of bacterial growth in Phase II studies.

项目摘要在与传染病作斗争时，世界正迅速迈向1940年前的情况。在全球范围内，抗菌耐药性是一个日益增长的问题，极大地阻碍了我们平息的能力全球流行病，例如结核病和疟疾，以及简单的葡萄球菌感染。拟议项目很重要，因为除非开发创新策略产生强大而有效的新类抗生素，医疗保健成本将继续攀升而且，即使是最常见的感染，我们将完全失去对抗的能力。当前的抗生素处理主要来自真菌和细菌产生的天然产物通常能够通过抑制细胞壁合成或维持来抑制其他生物的生长或通过抑制蛋白质合成。由于青霉素首先是通过弗莱明（Fleming）于1929年隔离的，所以大多数随后几代抗生素仍然与原始天然产品非常相似经过修改以增加更广泛的病原体的活动并减少其侧面效应曲线。恶唑酮，糖肽，-内酰胺和喹诺酮类未来，但革兰氏阴性细菌感染仍然是有问题的。多药耐药的病例（MDR，对2-3类的耐药性），广泛的耐药性（XDR，抗性，对大多数类除colistin或tigecycline以外的大多数类），甚至是PAN耐药性（PDR，对所有类别的抵抗力）近年来，医院细菌感染飙升，耐药药的出现分离株使这些感染越来越难以治疗。像这样的医院感染在美国所有医院的占4％，并且在病原体中的多种多样，抗生素抗性概况和严重程度。医院感染的一个重要原因是肠杆菌科家族，包括可能具有共生或致病性的革兰氏阴性杆菌。肠杆菌科有由于它们引起的感染的多样性，临床和经济影响会产生宽大的临床和经济影响；这个家庭导致许多感染，例如肺炎，血液感染（BSI），尿路感染（UTI）和内部腹部感染（IAIS）。世界卫生组织（WHO）列出了抗碳青霉烯肠杆菌科（CRE）在其优先病原体清单上对新型抗生素非常需要。因为这些耐药性感染的死亡率在30％至50％之间，并且存在如此困难在寻找可行的治疗方法时，必须解决对这些病原体的新疗法的需求。核酸是药物设计的有希望的途径，无论是治疗还是靶标。瞄准重力保守的RNA序列和结构，在细菌（肠杆菌科）中，参与增殖和细菌的存活是一种有前途的方法。使用我们的专有问题，测定和图书馆，我们为肠杆菌科中基本基因开发筛查测定法的建议。在这里，我们建议鉴定新型配体的创新计划，这些配体针对存在的mRNA 细菌中的必要基因，我们提出了一种生物物理筛选测定法，以鉴定这种情况配体。首先，如特定目标1所述，我们将表征一个模型核酸域商业上合成并识别特定和高亲和力的氨基加脂肪剂。然后我们将合成序列特异性的RNA结合配体，并筛选该靶向的缀合物库的序列特异性库结合和基因抑制。将使用报告基因测定法（特定的）确认作用机理目标2）。该方法的成功应用将使我们能够识别和验证铅化合物在II期研究中抑制细菌生长。