Aminoglycosides with reduced ototoxicity

具有降低耳毒性的氨基糖苷类

• 批准号: 10377538
• 负责人: DEV PRIYA ARYA
• 金额: $ 99.97万
• 依托单位: NUBAD, LLC
• 依托单位国家: 美国
• 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/10377538
• 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; Cessation of life; Chemistry; Clinical; Colistin; Communicable Diseases; Complex; Congresses; Coronavirus; Coupled; Creativeness; 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; Hospitals; 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 Microsomes; 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; Pneumonia; Population; Proliferating; 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; candidate identification; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; combat; cost; design; economic impact; efficacy study; extensive drug resistance; follow-up; guinea pig model; improved; in vivo; in vivo Model; inhibitor; innovation; method development; microorganism; mortality; multidisciplinary; novel; novel antibiotic class; novel therapeutic intervention; novel therapeutics; ototoxicity; pandemic influenza; pathogen; pathogenic bacteria; phase 1 study; pre-Investigational New Drug meeting; pre-clinical; preclinical toxicity; priority pathogen; rapid technique; rapid test; screening; small molecule; standard of care; success; synergism; tigecycline

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.

项目概要 氨基糖苷类药物是临床使用 70 多年来最便宜且众所周知的抗生素之一，但 它们的使用的主要限制之一是它们的耳毒性。我们正在开发快速且低成本的方法。 开发具有抗核糖体活性和降低毒性的氨基糖苷类药物在该项目中，我们将鉴定新的氨基糖苷类药物。 氨基糖苷类抗菌剂，其核糖体成分之间的复合物会降低耳毒性。 被用作小分子药物库的靶标，使核糖体失活，阻止细菌蛋白质 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，并提出了针对该问题的新颖解决方案的创造性步骤。 多重耐药（MDR，耐药2-3类）、广泛耐药（XDR、 对除粘菌素或替加环素之外的大多数类别的耐药性）甚至泛耐药性（PDR，对所有耐药性） 近年来，医院内细菌感染急剧上升，泛毒类药物的出现 耐药菌株使这些感染变得越来越难以治疗。 占美国所有住院时间的 4%，并且致病病原体极其多样化， 抗生素耐药性和严重程度是医院感染的一个重要原因。 家族，包括革兰氏阴性杆菌，可以是共生的或致病的。 由于该家族引起的感染多种多样，因此产生了广泛的临床和经济影响； 感染，如肺炎、血流感染 (BSI)、尿路感染 (UTI) 和腹腔内感染 世界卫生组织 (WHO) 列出了耐碳青霉烯类肠杆菌 (CRE)。 由于这些病原体的死亡率很高，因此迫切需要优先病原体清单上的新型抗生素。 耐药感染率在 30% 至 50% 之间，并且很难找到可行的治疗方法，因此需要 必须解决这些病原体的新疗法。 除非开发出创新策略来生产强效且有效的新型抗生素， 医疗保健费用将继续攀升，我们将完全失去对抗最常见疾病的能力 流感和冠状病毒（SARS 和 COVID-19）对靶向治疗的需求更加迫切。 与肺部感染相关的耐药细菌，例如碳青霉烯类耐药肠杆菌科细菌（CRE），这是一种常见的细菌 CRE 的例子是肺炎克雷伯菌 (KP)。前 CDC 主任 J. Gerberding 最近发表的文章。 指出，“患者受到 CRE、CR-A 和 CR-P 等超级细菌的威胁最大。 可引起肺部疾病的细菌病原体，是那些已经更容易患病的病原体 病毒性肺部感染，例如流感、严重急性呼吸道综合症 (SARS) 和 2009 H1N1。 例如，流感大流行夺走了全世界近 30 万人的生命，其中许多人死亡。 根据 CDC 的数据，29% 到 55% 之间的病例实际上是由继发性细菌性肺炎引起的。” 最近的研究（周， 来自武汉的《柳叶刀》2020, 395, 1054-1062）报道称，近 50% 的 COVID-19 与 死亡显示出继发性细菌感染（肺炎、败血症、血液感染）的证据。 需要做更多的工作来更好地了解继发细菌感染在 COVID-19 相关疾病中的作用 发病率，并同时制定无毒干预措施。 传染病研究的挑战之一是找到利用不断增加的知识的方法 研究疾病生物学、转化和进展的潜在机制，以开发新的疗法 针对 MDR、XDR 和 PDR 细菌感染的策略 40亿年前的细菌核糖体参与细菌的增殖和生存，是一种很有前途的细菌核糖体。 RNA 是核糖体的重要核酸成分，是药物设计的经过验证的目标。 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努力。 第一阶段研究中的合成、细菌抑制和斑马鱼筛选测定将在 使用豚鼠模型进行的体内功效和耳毒性研究的 II 期研究取得了成功。 这项工作将是对目前可用的抗菌治疗方法的重要补充。 新型氨基糖苷修饰、获得专利的 NUBAD 测定以及斑马鱼的初步结果 筛选试验和小鼠器官培养，以确定显示出降低的耳毒性的缀合物，打开 开发能够针对耐药病原体并大大改善治疗效果的氨基糖苷类药物的可能性 指数。