Development of peptide nucleic acid antibiotics

肽核酸抗生素的开发

• 批准号: 10347347
• 负责人: DEV PRIYA ARYA
• 金额: $ 99.96万
• 依托单位: NUBAD, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10347347
• 关键词: Abdominal Infection; Address; Amides; Amino Sugars; Aminoglycosides; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Bacillus; Bacteria; Bacterial Infections; Bacterial Pneumonia; Bacterial Proteins; Binding; Biodistribution; Biological Assay; Biological Availability; Biology; Books; COVID-19; COVID-19 mortality; Cavia; Cell Wall; Cells; Cessation of life; Chemicals; Clinical; Colistin; Communicable Diseases; Congresses; Coronavirus; Coupled; Creativeness; Data; Development; Disease; Dose; Drug Design; Drug Interactions; Drug Targeting; Drug resistance; Elements; Ensure; Enterobacteriaceae; Epidemic; Escherichia coli; Eukaryota; Face; Family; Follow-Up Studies; Gram-Negative Bacteria; Growth; Health Care Costs; In Vitro; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Institute of Medicine (U.S.); Intervention; Intra-abdominal; Klebsiella pneumoniae; Knowledge; L Forms; Lead; Left; Length of Stay; Libraries; Link; Locales; Lung diseases; Lung infections; Malaria; Membrane; Microbial Biofilms; Modeling; Multi-Drug Resistance; Mus; Nosocomial Infections; Nucleic Acid Binding; Nucleic Acids; Oligonucleotides; Organic Synthesis; Pathogenicity; Patients; Peptide Nucleic Acids; Peptides; Permeability; Pharmaceutical Preparations; Phase; Pneumonia; Predisposition; Prokaryotic Cells; Proliferating; Protein Biosynthesis; Protein Synthesis Inhibitors; RNA; RNA Binding; RNA Interference; RNA Sequences; RNA-targeting therapy; Rapid screening; Rattus; Reporting; Research; Resistance; Resistance profile; Ribosomal RNA; Ribosomes; Risk; Sepsis; Severe Acute Respiratory Syndrome; Severities; Societies; Solid; Specificity; Staphylococcal Infections; Structure; Superbug; Surgeon; Tail; Technology; Therapeutic; Thigh structure; Time; Tobramycin; Toxic effect; Translation Initiation; Tuberculosis; United States; United States National Academy of Sciences; Urinary tract infection; Viral; Work; World Health; World Health Organization; antibiotic resistant infections; antimicrobial; antimicrobial drug; antimicrobial resistant infection; bacterial resistance; base; candidate identification; carbapenem-resistant Enterobacteriaceae; combat; cost; design; drug development; economic impact; efficacy study; extensive drug resistance; fighting; improved; in vivo; inhibitor; innovation; microbial; mortality; multidisciplinary; novel; novel antibiotic class; novel therapeutic intervention; novel therapeutics; nucleic acid delivery; ototoxicity; pandemic influenza; pathogen; pathogenic bacteria; pre-Investigational New Drug meeting; pre-clinical; preclinical study; prevent; priority pathogen; screening; success; synergism; targeted agent; tigecycline; uptake

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 influenza, SARS, COVID-19, 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. Influenza and coronavirus (SARS and COVID-19) create an even more urgent need for targeting resistant bacteria related to lung infections, such as carbapenem-resistant Enterobacteriaceae (CRE), a common example of CRE being Klebsiella Pneumoniae (KP). Recent article by J. Gerberding, former CDC director states “The patients at greatest risk from superbugs like CRE and other bacterial pathogens that cause lung diseases, are the ones who are already more vulnerable to illness from viral lung infections like influenza, severe acute respiratory syndrome (SARS), and COVID-19. The 2009 H1N1 influenza pandemic, for example, claimed nearly 300,000 lives around the world. Many of those deaths — between 29% and 55% — were actually caused by secondary bacterial pneumonia, according to the CDC.” A recent study (Zhou, Lancet 2020, 395, 1054-1062) from Wuhan reports that almost 50% of COVID-19 related deaths showed evidence of secondary bacterial infections (pneumonia, sepsis, bloodstream infections). 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. One of the challenges of research in infectious diseases is to find ways to use the increasing knowledge of the mechanisms underlying disease biology, transformation and progression to develop novel therapeutic strategies targeting MDR, XDR, and PDR bacterial infections. Targeting heavily conserved RNA sequences and structures, present in the 4 billion years old bacterial ribosome, and involved in proliferation and survival of bacteria, is a promising approach. RNA, the essential nucleic acid component of the ribosome, is a validated target for drug design, both as therapeutic and as a target. We will target specific rRNA single strands, which are conserved across prokaryotes, essential for translation initiation but absent in eukaryotes, ensuring that a drug targeting this sequence can function as a broad spectrum therapeutic. In the proposed work, we will construct sequence- specific chemically modified rRNA targeting oligomers that can be effectively delivered inside the cell. Short RNA will be exploited as target for synthetic molecules that inactivate the functioning of the ribosome, stopping bacterial protein synthesis and causing bacterial death. NUBAD’s unique experimental approaches and technologies will allow us to target rRNA combinations not previously explored for susceptibility against bacteria. The work proposed is a multidisciplinary effort encompassing solid-phase organic synthesis, oligonucleotide stability and delivery, RNA targeted screening, antimicrobial activity, ADME TOX, and in vivo efficacy studies describes the development of sequence-specific cell permeable binders of rRNA. The success of the proposed work would be a significant addition to currently available ribosome-specific approaches in drug development. We propose using a small rRNA target sequence, heavily conserved in prokaryotes, to design conjugates that can be employed to inhibit microbial growth, opening possibilities for developing sequence-specific RNA targeted therapeutics. This work addresses an important world health issue, antimicrobial resistance, and presents creative steps towards a novel solution to this problem.

在抗击传染病方面，世界正迅速走向1940年前的局面。 抗生素耐药性是一个日益严重的问题，在全球范围内，极大地阻碍了我们的能力，以平息世界各地 流感、SARS、COVID-19、结核病和疟疾等流行病，以及单纯的疟疾， 感染除非开发出创新的策略来生产强大而有效的新型抗生素， 医疗保健费用将继续攀升，我们将完全失去打击最常见疾病的能力， 感染流感和冠状病毒（SARS和COVID-19）更迫切需要靶向治疗 与肺部感染相关的耐药细菌，如碳青霉烯耐药肠杆菌科（CRE），常见的 CRE的实例是克雷伯氏菌（KP）。前CDC主任J. Gerberding最近的一篇文章指出， “患者最容易受到CRE和其他导致肺部疾病的细菌病原体等超级细菌的感染， 是那些已经更容易受到病毒性肺部感染如流感，严重急性 呼吸综合征（SARS）和COVID-19。例如，2009年H1N1流感大流行造成近 全世界30万人的生命。其中29%到55%的死亡实际上是由 根据疾病控制中心的说法，继发性细菌性肺炎。”最近的一项研究（Zhou，Lancet 2020，395，1054-1062） 来自武汉的报告称，近50%的COVID-19相关死亡病例显示出继发性细菌感染的证据， 感染（肺炎、败血症、血流感染）。 多药耐药（MDR，耐2-3类）、广泛耐药（XDR，耐 大多数类别，除了粘菌素或替加环素），甚至泛耐药（PDR，耐所有类别） 近年来，医院内细菌感染激增， 分离株使这些感染越来越难以治疗。像这样的医院获得性感染 在美国，高达4%的住院时间，并且在致病病原体，抗生素 耐药性和严重性。医院感染的一个重要原因是肠杆菌科， 其包括可以是细菌性或致病性的革兰氏阴性杆菌。肠杆菌科有一个 广泛的临床和经济影响，由于感染的多样性，他们造成的;这个家庭造成许多 感染，如肺炎、血流感染（BSI）、尿路感染（UTI）和腹腔内感染。 感染（IAI）。世界卫生组织（WHO）列出了碳青霉烯类耐药肠杆菌科（CRE） 在他们的优先病原体名单上急需新型抗生素。因为死亡率的这些多 耐药感染在30%到50%之间，而且很难找到可行的治疗方法， 必须解决这些病原体的新疗法。 传染病研究的挑战之一是找到方法来利用越来越多的知识， 疾病生物学、转化和进展的潜在机制，以开发新的治疗策略 靶向MDR、XDR和PDR细菌感染。靶向高度保守的RNA序列和结构， 存在于40亿年前的细菌核糖体中，并参与细菌的增殖和存活，是一种 有前途的方法。核糖体的基本核酸成分RNA是药物的有效靶点， 设计，既作为治疗，也作为目标。我们将针对特定的rRNA单链，这是保守的 在原核生物中，这是翻译起始所必需的，但在真核生物中却不存在， 该序列可用作广谱治疗剂。在这项工作中，我们将构建序列- 特异性化学修饰的rRNA靶向寡聚体，其可以有效地递送到细胞内。短RNA 将被用作合成分子的靶点，这些合成分子可以抑制核糖体的功能， 细菌蛋白质合成并导致细菌死亡。NUBAD独特的实验方法和 技术将使我们能够靶向先前未探索的对细菌敏感性的rRNA组合。 这项工作是一个多学科的努力，包括固相有机合成，寡核苷酸 稳定性和递送、RNA靶向筛选、抗微生物活性、ADME TOX和体内功效研究 描述了rRNA的序列特异性细胞渗透性结合剂的开发。建议的成功 这项工作将是对药物开发中目前可用的核糖体特异性方法的重要补充。 我们建议使用在原核生物中高度保守的小rRNA靶序列来设计缀合物， 可用于抑制微生物生长，为开发序列特异性RNA靶向 治疗学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 创造性的步骤，以一种新的解决方案，这一问题。