权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Ototoxicity of modified aminoglycosides

修饰氨基糖苷类药物的耳毒性

基本信息

批准号：
10663352
负责人：
sandra Paige story
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：
2022
资助国家：
美国
起止时间：
2022-07-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663352
关键词：
Acute Address Affect Aminoglycoside Antibiotics Aminoglycosides Anti-Bacterial Agents Anti-Infective Agents Antibiotics Antifungal Agents Apical Auditory Auditory Brainstem Responses Bacteria Bacterial Infections Biodistribution Biological Biological Assay Biological Availability Biology Candida Candidiasis Cavia Cell Death Cell Wall Cells Chemistry Clinic Clinical Cochlea Containment Creativeness Data Detection Development Disease Dose Drug Interactions Drug Kinetics Drug toxicity Equilibrium Event Excretory function Feedback Fungal Drug Resistance Generations Growth Hair Cells Health Health Care Costs Human Immunocompromised Host In Vitro Incidence Individual Infection Knowledge Labyrinth Lead Legal patent Lethal Dose 50 Libraries Lipids Liver Microsomes Measurement Mechanoreceptors Medical Metabolic Metabolism Methods Microbe Microbial Biofilms Minimum Inhibitory Concentration measurement Modeling Modification Mus Mycoses National Institute of Allergy and Infectious Disease Natural regeneration Nosocomial Infections Organ Organ Culture Techniques Pathologic Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacodynamics Phase Population Prevention therapy Protocols documentation Pseudomonas Quality of life RNA Binding Rapid screening Renal function Research Resistance Resistance profile Risk-Benefit Assessment Role Sensory Hair Series Serum Signal Transduction Solid South Carolina Structure Testing Therapeutic Therapeutic Index Time Tobramycin Toxic effect Tuberculosis United States National Institutes of Health Universities Work absorption acute infection aminoglycoside-induced ototoxicity bacterial resistance base candidate identification combat cost cystic fibrosis patients design disability drug development economic cost efficacy study follow-up guinea pig model hearing impairment improved in vivo inhibitor innovation interest mechanical stimulus method development microbial mouse model multidisciplinary nephrotoxicity novel novel therapeutic intervention novel therapeutics ototoxicity pathogen pre-Investigational New Drug meeting pre-clinical preclinical toxicity preference prevent rapid technique screening screening program side effect small molecule small molecule libraries sound standard of care success synergism therapeutic development tuberculosis treatment

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. Although new generations of antibiotics have emerged in the last decades, aminoglycoside antibiotics maintain a leading role in treatment of acute infections and for specific indications such as tuberculosis or the containment of pseudomonas bacteria in patients with cystic fibrosis. Owing to their broad antibacterial spectrum and efficacy against resistant bacterial diseases, aminoglycoside antibiotics continue to be indispensable. However, their use has been limited due to side effects. The major side effects accompanying aminoglycoside treatment are nephrotoxicity and ototoxicity, including cochlear damage and vestibular disorders. Nephrotoxicity affects about 20% of patients and is usually reversible, while ototoxicity is irreversible. It is estimated that cochlear damage occurs in 20% and vestibular disorders in 15% of those receiving aminoglycoside antibiotics, but the incidence increases markedly to 80% in long-term treatment for tuberculosis. The pathological feature of aminoglycoside-induced ototoxicity is loss of mechanosensory hair cells in the inner ear. Hair cell loss begins at the base of the cochlea and proceeds toward the apex. Hair cells are specialized mechanoreceptors that convert auditory and vestibular mechanical stimuli into electrical signals. These cells are responsible for the detection of sound and equilibrium. Since mammalian hair cells lack the ability to regenerate, the loss of or damage to hair cells is the leading cause of permanent hearing impairments and vestibular disorders. Although a series of biological events and cell death pathways are known to be involved in aminoglycoside-induced hair cell death, no established clinical therapies for prevention or amelioration of this disability are available. Aminoglycoside-induced ototoxicity reduces the quality of life of millions of affected individuals and confers a great economic cost. Therefore, development of new efficacious synthetic aminoglycoside derivatives, but without the problematic side effects, will provide a fundamental approach to prevent ototoxicity. Since the ototoxicity potential and organ preference varies among the different aminoglycoside antibiotics, small changes in structure may greatly influence toxicity, providing great possibility to find new aminoglycoside derivatives. We are developing fast and low-cost methods to develop aminoglycosides with broad spectrum anti-infective activities, but with reduced ototoxicity. In this project, we will identify novel aminoglycoside based anti-infectives, that show reduced ototoxicity. This work addresses an important health issue, anti-infective drug ototoxicity, and presents creative steps towards a novel solution to this problem. Unless innovative strategies are developed to produce robust and effective new classes of non-toxic antibiotics, health care costs will continue to climb and we will completely lose our ability to combat even the most common infection. One of the challenges of research in drug development is to find ways to use the increasing knowledge of the mechanisms underlying disease biology, and toxicities, along with disease transformation and progression to develop novel therapeutic strategies for MDR, XDR, and PDR infections. One of the biggest bottlenecks in the advancement of drugs to the clinic and eventual limitation in the clinical usage, is the toxicity of the drug. This problem becomes even more acute when the drugs have to be used for extended periods of time (months), such as for fungal infections in immunocompromised patients. We have therefore focused our efforts in identifying the toxicity pathways for individual drug classes, such as aminoglycosides, and addressed these issues at the very outset. Since aminoglycoside-induced hair cell loss in explants is similar to that in humans, we will first use mouse organ culture for a secondary screening of the top compounds without toxicity. We will then use pigmented guinea pigs to evaluate auditory function by measurement of auditory brainstem responses, count loss of sensory hair cell loss, and assess renal function with serum for the top compounds. The results of this project will help us identify novel aminoglycosides with high efficacy against microbes of interest, but with reduced toxicity. The work proposed here, a multidisciplinary effort using rapid methods of synthesis, inhibition, and ototoxicity assays, will be further developed in this Phase II application using in vivo efficacy and ototoxicity studies using guinea pig models. We propose using novel aminoglycoside modifications, patented NUBAD assays, mouse organ culture studies, guinea pigs, to identify conjugates that show reduced ototoxicities, opening possibilities for developing drugs that can target resistant pathogens, but 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，但它们使用的主要限制是它们的耳毒性。尽管新一代的抗生素已经出现在在过去的几十年里，氨基糖苷类抗生素在治疗急性感染和特殊情况下一直占据主导地位。囊性纤维化患者的结核病或假单胞菌抑制等指征。由于其广谱的抗菌谱和对耐药细菌性疾病的疗效，氨基糖苷类药物抗生素仍然是不可或缺的。然而，由于副作用，它们的使用一直受到限制。主要方面氨基糖苷类药物治疗的副作用是肾毒性和耳毒性，包括耳蜗病。以及前庭功能障碍。肾毒性影响约20%的患者，通常是可逆的，而耳毒性是不可逆转的。据估计，在这些人中，20%的人耳蜗会受损，15%的人会出现前庭功能障碍接受氨基糖苷类抗生素治疗，但长期治疗后发病率显著上升至80%。肺结核。氨基糖苷类耳毒性的病理特征是机械性毛发脱落内耳中的细胞。毛细胞的丢失开始于耳蜗底，并向顶端进发。毛细胞是专门的机械感受器，将听觉和前庭机械刺激转化为电信号。这些细胞负责检测声音和平衡。因为哺乳动物的毛细胞缺乏再生能力、毛细胞的丧失或损伤是永久性听力障碍的主要原因以及前庭功能障碍。尽管已知涉及一系列生物事件和细胞死亡途径在氨基糖苷类药物所致的毛细胞死亡中，尚无既定的临床治疗方法来预防或改善这种情况。残障人士可供选择。氨基糖苷类耳毒性降低数百万患者的生活质量这会给个人带来巨大的经济代价。因此，开发新的高效合成材料氨基糖苷衍生物，但没有问题的副作用，将提供一种基本的方法来治疗预防耳毒性。由于耳毒性潜在性和器官偏好性在不同的氨基糖苷类抗生素，结构上的微小变化可能会对毒性产生很大影响，提供了很大的可能性寻找新的氨基糖苷衍生物。我们正在开发快速和低成本的方法来开发氨基糖苷类化合物具有广谱抗感染活性，但降低了耳毒性。在这个项目中，我们将鉴定新型氨基糖苷类抗感染药物，具有降低耳毒性的作用。这项工作解决了一个重要的健康问题，抗感染药物耳毒性，并提出了创造性的步骤，以此为新的解决方案有问题。除非开发出创新的战略来生产强大而有效的新型无毒抗生素，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。药物开发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和毒性以及疾病转化和进展的潜在机制为MDR、XDR和PDR感染开发新的治疗策略。最大的瓶颈之一是药物进入临床并最终限制临床使用的，就是药物的毒性。当药物必须长时间(几个月)使用时，这个问题变得更加严重，例如对免疫功能低下患者的真菌感染。因此，我们将努力集中在确定个别药物类别的毒性途径，如氨基糖苷类，并解决这些问题一开始就有问题。由于氨基糖苷类药物在外植体中引起的毛细胞丢失与人类相似，我们将首先使用小鼠器官培养对无毒性的顶级化合物进行二次筛选。我们会然后用有色豚鼠通过测量听性脑干反应来评估听觉功能，计算感觉毛细胞丢失的数量，并用血清评估顶级化合物的肾功能。结果是该项目将帮助我们确定对感兴趣的微生物具有高效疗效的新型氨基糖苷类药物，但降低了毒性。这里提出的工作是一项多学科的努力，使用快速合成、抑制和耳毒性的方法在这一第二阶段的应用中，将进一步开发使用体内疗效和耳毒性研究的检测方法豚鼠模型。我们建议使用新的氨基糖苷类修饰，专利的NUBAD分析，小鼠器官培养研究，豚鼠，以确定显示降低耳毒性的结合物，打开了可能性用于开发针对耐药病原体的药物，但治疗指数有很大改善。