Development of peptide nucleic acid antibiotics

肽核酸抗生素的开发

基本信息

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
项目类别：
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

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

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项目摘要

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，抗菌抗性是一个日益严重的问题，极大地阻碍了我们在全球范围内平息的能力流行病，例如影响力，SARS，COVID-19，结核病和疟疾，以及简单的葡萄球菌感染。除非制定创新策略来生产强大而有效的新类抗生素，否则医疗保健成本将继续攀升，我们将完全失去与最常见的能力作战的能力感染。流感和冠状病毒（SARS和COVID-19）创造了更加迫切的目标与肺部感染有关的抗性细菌，例如碳苯甲酸肠杆菌科（CRE），一种常见 Cre是肺炎克雷伯氏菌（KP）的例子。疾病预防控制中心总监说，J。Gerberding的最新文章 “来自CRE和其他引起肺部疾病的细菌病原体等超级细菌风险最大的患者，那些已经更容易受到病毒肺部感染的疾病的人，例如影响，严重急性呼吸综合征（SARS）和Covid-19。例如，2009 H1N1影响力大流行几乎声称世界各地有30万。实际上，许多死亡人数在29％至55％之间。根据疾病预防控制中心的次要细菌性肺炎。”最近的一项研究（Zhou，Lancet 2020，395，1054-1062）从武汉报道说，近50％的Covid-19相关死亡显示了次生细菌的证据感染（肺炎，败血症，血液感染）。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。像这些帐户这样的医院可获得的感染最多4％在美国住院，并且在病原体，抗生素方面非常多样化电阻概况和严重性。医院感染的一个重要原因是肠杆菌科家族，其中包括可能具有共生或致病性的革兰氏阴性杆菌。肠杆菌科有一个由于它们引起的感染的多样性，广泛的临床和经济影响；这个家庭导致许多感染，例如肺炎，血液感染（BSIS），尿路感染（UTI）和腹腔内感染（IAIS）。世界卫生组织（WHO）列出了耐碳青霉烯的肠杆菌科（CRE）因为在其优先病原体清单上非常需要新型抗生素。因为这些多人的死亡率耐药感染在30％至50％之间，很难找到可行的治疗方法，需要对于这些病原体的新疗法，必须解决。传染病研究的挑战之一是找到越来越多的知识的方法疾病生物学的基础机制，转化和发展以发展新型治疗策略靶向MDR，XDR和PDR细菌感染。靶向大量构成RNA序列和结构，存在于40亿年历史的核糖体中，并参与细菌的增殖和存活，是一个有希望的方法。 RNA是核糖体的必需核酸成分，是药物的验证靶标设计，无论是治疗性还是目标。我们将瞄准特定的rRNA单链，这些链是保守的整个原核生物，对于翻译开始至关重要，但在真核生物中不存在，以确保靶向药物该序列可以充当广泛的疗法。在拟议的工作中，我们将构建序列 - 特定的化学修饰rRNA靶向低聚物，可以有效地在细胞内传递。短RNA 将探索作为灭活核糖体功能的合成分子的靶标细菌蛋白质合成并引起细菌死亡。努巴德独特的实验方法和技术将使我们能够靶向以前未探索的RRNA组合，以易于对细菌的敏感性。提出的工作是一项多学科的努力，包括固态有机合成，寡核苷酸稳定性和递送，RNA靶向筛查，抗菌活性，ADME TOX和体内效率研究描述了rRNA的序列特异性细胞可渗透粘合剂的发展。提议的成功对于当前可用的核糖体特异性方法，工作将是药物开发中的重要补充。我们建议使用一个小的rRNA靶序列，在原核生物中大量保守，以设计结合。可以用来抑制微生物生长，开辟了开发针对序列特异性RNA的可能性治疗。这项工作解决了一个重要的世界卫生问题，抗菌素的抵抗和呈现迈向解决这个问题的新颖解决方案的创造性步骤。