Aminoglycosides with reduced ototoxicity

具有降低耳毒性的氨基糖苷类

• 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
• 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

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.

项目总结 氨基糖苷类抗生素是临床上使用了70多年的最便宜和最知名的抗生素之一，但 使用它们的主要限制之一是它们的耳毒性。我们正在开发快速和低成本的方法来 开发具有抗核糖体活性和降低毒性的氨基糖苷类药物。在这个项目中，我们将确定新的 氨基糖苷类抗菌药，显示出降低的耳毒性。核糖体成分之间的复合体将是 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 在减少毒性的同时，合成并导致细菌死亡。这项工作解决了一个重要的健康问题， 抗生素耳毒性，并提出了创造性的步骤，为这一问题的新解决方案。 多药耐药(MDR，耐2-3类)、广泛耐药(XDR、 对除粘菌素或替吉环素以外的大多数类别耐药)，甚至对PAN耐药(PDR，对所有 近年来，医院内细菌感染激增，泛药物的出现- 耐药菌株正在使这些感染变得越来越难以治疗。这样的医院获得性感染 占美国住院总人数的4%，其致病病原体极其多样， 抗生素耐药性概况和严重程度。引起医院感染的一个重要原因是肠杆菌科细菌。 家庭，其中包括革兰氏阴性杆菌，可以共生或致病。肠杆菌科有一种 由于它们引起的感染的多样性，造成广泛的临床和经济影响；这个家庭导致许多 肺炎、血流感染(BSI)、尿路感染(UTI)和腹内感染 感染(IAI)。世界卫生组织(WHO)将耐碳青霉烯类肠杆菌科(CRE)列入名单 因为他们的优先病原体名单上迫切需要新的抗生素。因为这些多人的死亡率 耐药感染在30%到50%之间，而且很难找到可行的治疗方法，需要 对于这些病原体的新疗法，必须加以解决。 除非开发出创新的策略来生产强大而有效的新类别抗生素， 医疗费用将继续攀升，我们将完全失去与最常见的疾病作斗争的能力 感染。流感和冠状病毒(非典和新冠肺炎)产生了更迫切的目标需求 与肺部感染有关的耐药细菌，如碳青霉烯类耐药肠杆菌科(CRE)，一种常见的 Cre为肺炎克雷伯氏菌(Kp)。疾病控制与预防中心前主任J·格伯丁最近的一篇文章 国家规定，“最有可能感染CRE、CR-A等超级细菌的患者。Buamanii和CR-P。铜绿假单胞菌等 可以导致肺部疾病的细菌病原体，是那些已经更容易受到来自 病毒性肺部感染，如流感、严重急性呼吸综合征(SARS)和新冠肺炎。2009年甲型H1N1流感 例如，流感大流行夺走了世界各地近30万人的生命。其中许多人的死亡- 根据疾控中心的数据，29%到55%的人实际上是由继发性细菌性肺炎引起的。一个 最近的研究(周， 来自武汉的《柳叶刀》报道称，近50%的新冠肺炎与 死亡显示有继发性细菌感染(肺炎、败血症、血流感染)的证据。显然， 需要做更多的工作来更好地了解继发性细菌感染在新冠肺炎相关疾病中的作用 并同时开发无毒干预措施。 传染病研究的挑战之一是找到利用日益增长的知识的方法 疾病生物学、转化和进展的潜在机制，以开发新的治疗方法 MDR、XDR和PDR细菌感染的策略。靶向高度保守的RNA结构，存在于 已有40亿年历史的细菌核糖体，参与了细菌的增殖和生存，是一种很有前途的 接近。Rna是核糖体的基本核酸成分，是药物设计的有效靶点，两者 作为一种治疗手段和靶子。这里提出的工作是一项多学科的努力，使用快速方法 第一阶段研究中的合成、抑菌和斑马鱼筛选试验将在#年进一步发展。 第二阶段使用豚鼠模型进行体内疗效和耳毒性研究。建议的成功 这项工作将是对目前抗菌治疗方法的重大补充。我们建议使用 新的氨基糖苷类修饰、获得专利的NUBAD分析和斑马鱼的初步结果 筛选试验和小鼠器官培养以确定显示降低耳毒性的结合物，开放 开发可针对耐药病原体的氨基糖苷类药物的可能性 指数。