Development of Peptide Antibiotic Nucleic Acids

肽类抗生素核酸的开发

• 批准号: 8780584
• 负责人: DEV PRIYA ARYA
• 金额: $ 29.58万
• 依托单位: NUBAD, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-20 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780584
• 关键词: Address; Amino Sugars; Aminoglycosides; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Awareness; Bacteria; Bacterial Infections; Bacterial Proteins; Base Pairing; Binding; Biological Assay; Books; Boston; Bypass; Cell Line; Cell physiology; Cells; Cessation of life; Communicable Diseases; Complement; Complex; Congresses; Development; Disease; Drug Design; Drug Targeting; Drug resistance; Enzymes; Epidemic; Escherichia coli; Generations; Growth; Head; Health Care Costs; High Pressure Liquid Chromatography; Human; Hybrids; In Vitro; Infection; Institute of Medicine (U.S.); Knowledge; Lead; Libraries; Link; Locales; Malaria; Marketing; Methods; Neomycin; Nosocomial Infections; Nucleic Acids; Organic Synthesis; Parasites; Peptide Antibiotics; Peptide Nucleic Acids; Pharmaceutical Preparations; Phase; Predisposition; Preparation; Protein Biosynthesis; RNA Binding; RNA Interference; Reporting; Research; Resistance; Ribosomal RNA; Ribosomes; Site; Solid; Solutions; Specificity; Staphylococcal Infections; Structure; Surgeon; Tail; Technology; Testing; Therapeutic; Thiourea; Time; Toxic effect; Translations; Tuberculosis; United States; United States National Academy of Sciences; Universities; Validation; Virus; Work; World Health; antimicrobial; antimicrobial drug; bacterial resistance; combat; comparative; cost; design; fighting; innovation; microorganism; multidisciplinary; novel; novel therapeutics; public health relevance; scale up; screening; small molecule; success; therapeutic target; uptake; web site

DESCRIPTION (provided by applicant): One of the challenges of research in infectious diseases is to find ways to use the increasing knowledge of the mechanisms underlying disease transformation and progression to develop novel therapeutic strategies for diseases such as increasing menace of bacterial infections. Targeting specific RNA, such as rRNA which are involved in proliferation and survival of bacteria is a promising approach. 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. 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. Nucleic acids are avenues for drug design, both as therapeutics and as targets. Here we propose to establish new methods for identifying antibiotic ribosome targets and lead compounds. We are developing fast and low cost methods to screen sequence-specific small molecules for novel anti-ribosomal activities. We will construct sequence-specific ribosomal targeting oligomers as antibacterials. Complexes between ribosomal components will be exploited as targets for small molecule drug libraries that- inactivate the ribosome, stopping bacterial protein synthesis and causing bacterial death. NUBADs unique experimental approaches and technologies will allow us to target ribosomal regions not previously explored for susceptibility against anti-bacterial agents. This work addresses an important world health issue, antimicrobial resistance, and presents creative steps towards a novel solution to this problem. The work proposed here, a multidisciplinary effort encompassing solid-phase organic synthesis, RNA targeted screening and antibacterial studies, describes the development of sequence-specific cell permeable binders of rRNA as antibacterial therapeutics. The success of the proposed work would be a significant addition to currently available ribosome-specific approaches in antibacterial therapy. We propose using a small rRNA target sequences to design conjugates that can be employed to inhibit bacterial growth, opening possibilities for developing sequence-specific RNA targeted therapeutics.

描述（由申请人提供）：感染性疾病研究的挑战之一是找到方法，利用对疾病转化和进展机制的日益增加的了解，为疾病（如细菌感染的威胁增加）开发新的治疗策略。靶向参与细菌增殖和存活的特异性RNA（如rRNA）是一种有前途的方法。在抗击传染病方面，世界正迅速走向1940年前的局面。抗生素耐药性是全球范围内一个日益严重的问题，极大地阻碍了我们遏制结核病和疟疾等全球流行病以及简单的疟疾感染的能力。除非开发出创新的战略来生产强大而有效的新型抗生素，否则医疗保健成本将继续攀升，我们将完全失去对抗最常见感染的能力。 核酸是药物设计的途径，既作为治疗剂又作为靶点。在这里，我们建议建立新的方法来识别抗生素核糖体靶标和先导化合物。我们正在开发快速和低成本的方法来筛选新的抗核糖体活性的序列特异性小分子。我们将构建序列特异性核糖体靶向寡聚体作为抗菌剂。核糖体组分之间的复合物将被开发为小分子药物文库的靶标，这些药物文库可以抑制核糖体，停止细菌蛋白质合成并引起细菌感染。 死亡NUBAD独特的实验方法和技术将使我们能够靶向以前未探索过的对抗菌剂敏感的核糖体区域。这项工作解决了一个重要的世界卫生问题，抗菌素耐药性，并提出了创造性的步骤，以解决这一问题的新方法。 这里提出的工作，一个多学科的努力，包括固相有机合成，RNA靶向筛选和抗菌研究，描述了序列特异性的细胞渗透性结合剂的rRNA抗菌治疗的发展。拟议工作的成功将是对目前可用的核糖体特异性抗菌治疗方法的重要补充。我们建议使用小rRNA靶序列来设计可用于抑制细菌生长的缀合物，从而为开发序列特异性RNA靶向治疗剂开辟了可能性。