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.

项目摘要 氨基糖苷类抗生素是最便宜的和众所周知的抗生素之一，在临床上使用了70多年，但 它们使用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， 开发具有抗核糖体活性和降低毒性的氨基糖苷类。在这个项目中，我们将确定新的 氨基糖苷类抗菌药物，其显示降低的耳毒性。核糖体成分之间的复合物将被 被用作小分子药物库的靶点，这些药物库可以抑制核糖体，阻止细菌蛋白 合成并导致细菌死亡，同时降低毒性。这项工作涉及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，对这个问题的一个新的解决方案。 多药耐药（MDR，耐2-3类）、广泛耐药（XDR， 对除粘菌素或替加环素外的大多数类别的耐药性）甚至泛耐药性（PDR，对所有 近年来，医院细菌感染急剧上升，泛药物- 耐药菌株使这些感染越来越难以治疗。 占美国所有住院人数的4%，并且致病病原体的多样性令人难以置信， 抗生素耐药性特征和严重程度。医院感染的一个重要原因是肠杆菌科 革兰氏阴性杆菌科，包括革兰氏阴性杆菌，可以是细菌性或致病性的。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。 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）。美国疾病控制和预防中心前主任杰伯丁最近的一篇文章 他说：“患者最有可能感染超级细菌，如CRE，CR-A。Buamanii和CR-P. aeruginosa和其他 细菌病原体，可以导致肺部疾病，是那些谁已经更容易受到疾病， 病毒性肺部感染，如流感、严重急性呼吸道综合征（SARS）和COVID-19。2009年H1N1 例如，流感大流行在全世界夺去了近30万人的生命。其中许多死亡- 根据疾病预防控制中心的数据，29%到55%的人实际上是由继发性细菌性肺炎引起的。”一 最近的研究（周， Lancet 2020，395，1054-1062）报告称，近50%的COVID-19相关 死亡表明有继发性细菌感染的证据（肺炎、败血症、血流感染）。很显然， 需要做更多的工作，以更好地了解继发性细菌感染在COVID-19相关疾病中的作用。 发病率，并同时开发无毒干预措施。 传染病研究面临的挑战之一是如何利用日益增长的知识 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 40亿年前的细菌核糖体，参与细菌的增殖和生存，是一个有前途的 approach. RNA是核糖体的基本核酸成分，是药物设计的有效靶点， 作为治疗和目标。这里提出的工作，一个多学科的努力，使用快速的方法， 合成，细菌抑制和斑马鱼筛选试验在第一阶段的研究，将进一步发展， II期使用豚鼠模型进行的体内疗效和耳毒性研究。建议的成功 这项工作将是对目前可用的抗菌治疗方法的重要补充。我们建议使用 新颖的氨基糖苷类药物修饰，获得专利的NUBAD检测，以及斑马鱼的初步结果 筛选测定和小鼠器官培养以鉴定显示降低的耳毒性、开放性和抗氧化性的缀合物， 开发氨基糖苷类药物的可能性， 指数。