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.

项目摘要氨基糖苷是70多年来临床用途中最便宜，最著名的抗生素之一，但它们使用的主要局限性是它们的耳毒性。尽管新一代的抗生素已经出现在最近几十年，氨基糖苷抗生素在治疗急性感染和特定方面保持领先作用囊性纤维化患者中的结核病或假单胞菌细菌的适应症。由于它们的广泛抗菌光谱和抗性细菌疾病的功效，氨基糖苷抗生素仍然是必不可少的。但是，由于副作用，它们的使用受到限制。主要方面伴随氨基糖苷治疗的作用是肾毒性和耳毒性，包括人工耳蜗损伤和前庭疾病。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，人工耳蜗损害发生在20％，前庭疾病中有15％接受氨基糖苷的抗生素，但长期治疗中的发病率显着增加到80％结核。氨基糖苷诱导的耳毒性的病理特征是机械感觉的损失内耳中的细胞。毛细胞的损失始于耳蜗的底部，并朝着顶点进行。毛细胞是将听觉和前庭机械刺激转换为电信号的专门机械感受器。这些细胞负责检测声音和平衡。由于哺乳动物毛细胞缺乏能够再生，损坏或损坏毛细胞是永久性听力障碍的主要原因和前庭疾病。尽管已知一系列生物事件和细胞死亡途径涉及在氨基糖苷诱导的毛细胞死亡中，没有建立的临床疗法来预防或改善这种疗法残疾可用。氨基糖苷诱导的耳毒性降低了数百万受影响的生活质量个人并赋予了巨大的经济成本。因此，开发新的有效合成氨基糖苷衍生物，但没有问题的副作用，将提供一种基本的方法防止耳毒性。由于耳毒性潜力和器官偏好在不同的氨基糖苷抗生素，结构的微小变化可能会极大地影响毒性，从而极大地可能找到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具有广谱抗感染活性的氨基糖苷，但耳毒性降低。在这个项目中，我们将识别基于氨基糖苷的新型抗感染物，显示出降低的耳毒性。这项工作解决了重要的健康问题，抗感染药物耳毒性，并提出了新的解决方案的创造性步骤问题。除非开发创新策略来生产强大而有效的新类无毒抗生素，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。药物开发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和毒性的基础机制以及疾病转化和进展开发用于MDR，XDR和PDR感染的新型治疗策略。最大的瓶颈之一药物提高到诊所的发展，最终在临床使用中的限制是药物的毒性。当必须长时间使用药物（月份）时，这个问题变得更加敏锐例如免疫功能低下患者的真菌感染。因此，我们将精力集中在确定单个药物类别（例如氨基糖苷）的毒性途径，并解决这些毒物类别从一开始就有问题。由于外植体中氨基糖苷诱导的毛细胞损失与人类相似，因此我们将首先将小鼠器官培养物进行辅助筛选而没有毒性。我们将然后使用有色的豚鼠来评估听觉脑干反应的听觉功能，计算感觉毛细胞损失的丧失，并用血清评估顶部化合物的肾功能。结果该项目将帮助我们确定对感兴趣的微生物具有高效率的新型氨基糖苷剂，但毒性降低。这里提出的工作是使用快速的合成，抑制和耳毒性方法的多学科工作在此II阶段应用中，使用体内功效和耳毒性研究将进一步开发分析。豚鼠模型。我们建议使用新型的氨基糖苷修饰，获得专利的NUBAD分析，小鼠器官培养研究，豚鼠，以识别显示降低耳毒性的共轭物，开放可能性用于开发可以靶向抗性病原体但治疗指数大大改善的药物。