Aminoglycosides with reduced ototoxicity

具有降低耳毒性的氨基糖苷类

基本信息

批准号：
10156973
负责人：
DEV PRIYA ARYA
金额：
$ 100万
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：
2020-08-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10156973
关键词：
ADME Study Abdominal Infection Address Amikacin Aminoglycosides Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antimicrobial Resistance Auditory Auditory Brainstem Responses Awareness Bacillus Bacteria Bacterial Infections Bacterial Pneumonia Bacterial Proteins Biodistribution Biological Assay Biological Availability Biology Books COVID-19 COVID-19 morbidity COVID-19 mortality Cavia Cell Wall Centers for Disease Control and Prevention (U.S.)Cessation of life Chemistry Clinical Colistin Communicable Diseases Complex Congresses Coronavirus Coupled Development Disease Dose Drug Design Drug Interactions Drug Kinetics Drug Targeting Drug resistance Enterobacteriaceae Excretory function Family Feedback Fiber Growth Hair Cells Health Health Care Costs Human Infection Influenza Influenza A Virus, H1N1 Subtype Institute of Medicine (U.S.)Intervention Intra-abdominal Klebsiella pneumoniae Knowledge L Forms Lead Legal patent Length of Stay Lethal Dose 50 Libraries Liver Lung diseases Lung infections Measurement Medical Metabolism Methods Microbial Biofilms Minimum Inhibitory Concentration measurement Modeling Modernization Modification Multi-Drug Resistance Mus Nosocomial Infections Nucleic Acids Organ Culture Techniques Parasites Pathogenicity Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacodynamics Phase Pigments Pneumonia Population Protein Biosynthesis Protocols documentation Pseudomonas aeruginosa RNA RNA Binding Rapid screening Rattus Renal function Reporting Research Resistance Resistance profile Ribosomes Risk Risk-Benefit Assessment Role Sensory Hair Sepsis Serum Severe Acute Respiratory Syndrome Severities Societies Solid South Carolina Structure Superbug Surgeon Testing Therapeutic Therapeutic Index Thigh structure Time Toxic effect United States United States National Academy of Sciences Universities Urinary tract infection Viral Virus Work World Health Organization Zebrafish absorption aminoglycoside-induced ototoxicity antibiotic resistant infections antimicrobial drug antimicrobial resistant infection bacterial resistance carbapenem resistance carbapenem-resistant Enterobacteriaceae combat cost design economic impact efficacy study extensive drug resistance follow-up improved in vivo in vivo Model inhibitor/antagonist innovation meetings method development microorganism mortality multidisciplinary novel novel therapeutic intervention novel therapeutics ototoxicity pandemic influenza pathogen pathogenic bacteria phase 1 study porcine model pre-clinical preclinical toxicity priority pathogen rapid technique rapid test screening small molecule standard of care success synergism tigecycline

ADME Study Abdominal Infection Address Amikacin Aminoglycosides Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antimicrobial Resistance Auditory Auditory Brainstem Responses Awareness Bacillus Bacteria Bacterial Infections Bacterial Pneumonia Bacterial Proteins Biodistribution Biological Assay Biological Availability Biology Books COVID-19 COVID-19 morbidity COVID-19 mortality Cavia Cell Wall Centers for Disease Control and Prevention (U.S.)Cessation of life Chemistry Clinical Colistin Communicable Diseases Complex Congresses Coronavirus Coupled Development Disease Dose Drug Design Drug Interactions Drug Kinetics Drug Targeting Drug resistance Enterobacteriaceae Excretory function Family Feedback Fiber Growth Hair Cells Health Health Care Costs Human Infection Influenza Influenza A Virus, H1N1 Subtype Institute of Medicine (U.S.)Intervention Intra-abdominal Klebsiella pneumoniae Knowledge L Forms Lead Legal patent Length of Stay Lethal Dose 50 Libraries Liver Lung diseases Lung infections Measurement Medical Metabolism Methods Microbial Biofilms Minimum Inhibitory Concentration measurement Modeling Modernization Modification Multi-Drug Resistance Mus Nosocomial Infections Nucleic Acids Organ Culture Techniques Parasites Pathogenicity Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacodynamics Phase Pigments Pneumonia Population Protein Biosynthesis Protocols documentation Pseudomonas aeruginosa RNA RNA Binding Rapid screening Rattus Renal function Reporting Research Resistance Resistance profile Ribosomes Risk Risk-Benefit Assessment Role Sensory Hair Sepsis Serum Severe Acute Respiratory Syndrome Severities Societies Solid South Carolina Structure Superbug Surgeon Testing Therapeutic Therapeutic Index Thigh structure Time Toxic effect United States United States National Academy of Sciences Universities Urinary tract infection Viral Virus Work World Health Organization Zebrafish absorption aminoglycoside-induced ototoxicity antibiotic resistant infections antimicrobial drug antimicrobial resistant infection bacterial resistance carbapenem resistance carbapenem-resistant Enterobacteriaceae combat cost design economic impact efficacy study extensive drug resistance follow-up improved in vivo in vivo Model inhibitor/antagonist innovation meetings method development microorganism mortality multidisciplinary novel novel therapeutic intervention novel therapeutics ototoxicity pandemic influenza pathogen pathogenic bacteria phase 1 study porcine model pre-clinical preclinical toxicity priority pathogen rapid technique rapid test screening small molecule standard of care success synergism tigecycline

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项目摘要

PROJECT SUMMARY Aminoglycosides are one of the cheapest and well-known antibiotics in clinical use for over 70 years, but one of the major limitations in their use is their ototoxicity. We are developing fast and low-cost methods to develop aminoglycosides with anti-ribosomal activities and reduced toxicity. In this project, we will identify novel aminoglycoside antibacterials, that show reduced ototoxicity. 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 while reducing toxicity. This work addresses an important health issue, antibiotic ototoxicity, and presents creative steps towards a novel solution to this problem. 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. 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). A recent article by J. Gerberding, former CDC director states, “The patients at greatest risk from superbugs like CRE, CR-A. buamanii and CR-P. aeruginosa and other bacterial pathogens that can 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). Clearly, more work needs to be done to better understand the role of secondary bacterial infections in COVID-19 related morbidities, and develop non-toxic interventions in parallel. 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 for MDR, XDR, and PDR bacterial infections. Targeting heavily conserved RNA 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. The work proposed here, a multidisciplinary effort using rapid methods of synthesis, bacterial inhibition and zebrafish screening assays in Phase I studies, will be further developed in Phase II using in vivo efficacy and ototoxicity studies using guinea pig models. The success of the proposed work would be a significant addition to currently available approaches in antibacterial therapy. We propose using novel aminoglycoside modifications, patented NUBAD assays, and preliminary results from a zebrafish screening assay and mouse organ culture to identify conjugates that show reduced ototoxicities, opening possibilities for developing aminoglycosides that can target resistant pathogens with much improved therapeutic indices.

项目摘要氨基糖苷是临床用途中最便宜，最著名的抗生素之一，但是使用的主要局限性之一是它们的耳毒性。我们正在开发快速和低成本的方法开发具有抗红细胞活性并降低毒性的氨基糖苷。在这个项目中，我们将确定小说氨基糖苷抗菌剂，表现出降低的耳毒性。核糖体成分之间的复合物将是被利用为小分子药物库的目标，使核糖体灭活，停止细菌蛋白合成并导致细菌死亡，同时降低毒性。这项工作解决了一个重要的健康问题，抗生素耳毒性，并为解决这个问题的新颖解决方案提出了创造性的步骤。多药耐药的病例（MDR，对2-3类的耐药性），广泛的耐药性（XDR，除了colistin或tigecycline以外的大多数类别），甚至抗药性耐药性（PDR，对所有人的耐药性）近年来，类的医学院细菌感染激增，泛药的出现抗性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。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。前CDC主任J. Gerberding最近的一篇文章指出：“从CRE，CR-A。Buamanii和Cr-P。Aeruginosa等超级细菌的患者都有很大的风险可能引起肺部疾病的细菌病原体，已经更容易受到疾病的疾病病毒肺部感染，如流感，严重的急性呼吸综合征（SARS）和Covid-19。 2009 H1N1 例如，影响力大流行声称世界各地有近30万寿命。其中许多死亡 - 根据疾病预防控制中心的说法，实际上是由继发细菌肺炎引起的29％至55％。”一个最近的研究（周，武汉（Wuhan）的《柳叶刀2020，395，1054-1062》报告说，近50％的covid-19 死亡显示了继发性细菌感染（肺炎，败血症，血液感染）的证据。清楚地，需要做更多的工作，以更好地了解次生细菌感染在COVID-19相关的作用病毒性，并并行发展无毒干预措施。传染病研究中研究的挑战之一是找到使用不断增长的知识的方法疾病生物学的基础机制，发展新疗法的转化和发展 MDR，XDR和PDR细菌感染的策略。靶向大量构成RNA结构，存在于 40亿年的细菌核糖体，参与细菌的增殖和存活，是一个有前途的方法。 RNA是核糖体的必需核酸成分，是药物设计的验证靶标，两者都作为治疗和目标。这里提出的工作是使用快速方法的多学科工作在I期研究中的合成，细菌抑制和斑马鱼筛查测定法将进一步发展使用豚鼠模型的体内效率和耳毒性研究的II期。提议的成功工作将是当前可用的抗菌治疗方法的重要补充。我们建议使用新型的氨基糖苷修饰，获得专利的NUBAD分析和斑马鱼的初步结果筛选测定和小鼠器官培养物以识别显示降低耳毒性的共轭物，开放开发可以通过大大改善治疗的抗糖苷的氨基糖苷的可能性指数。