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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，其使用的主要限制是其耳毒性。虽然新一代的抗生素已经出现，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异性适应症，如结核病或囊性纤维化患者的假单胞菌感染。由于其广泛的抗菌谱和对耐药性细菌疾病的功效，氨基糖苷类抗生素抗生素仍然是必不可少的。然而，由于副作用，其使用受到限制。主侧氨基糖苷类药物治疗的副作用是肾毒性和耳毒性，包括耳蜗损伤和前庭障碍。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，耳蜗损伤发生在20%和前庭障碍的15%，接受氨基糖苷类抗生素，但在长期治疗中，结核氨基糖甙类药物引起的耳毒性的病理特征是机械感觉毛的丢失内耳的细胞。毛细胞的损失开始于耳蜗的底部，并向顶端进行。毛细胞是将听觉和前庭机械刺激转化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。由于哺乳动物的毛细胞缺乏再生能力，毛细胞的损失或损害是永久性听力障碍的主要原因和前庭障碍。尽管已知一系列生物学事件和细胞死亡途径与在氨基糖苷类药物诱导的毛细胞死亡中，没有建立预防或改善这种死亡的临床疗法。残疾人是可用的。氨基糖苷类抗生素诱导的耳毒性降低了数百万受影响者的生活质量这给个人带来了巨大的经济成本。因此，开发新的有效合成氨基糖苷类衍生物，但没有问题的副作用，将提供一个基本的方法，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类抗生素，结构的微小变化可能会极大地影响毒性，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具有广谱抗感染活性但耳毒性降低的氨基糖苷类。在这个项目中，我们将鉴定新的基于氨基糖苷类的抗感染药物，其显示降低的耳毒性。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，朝着一个新的解决办法，这一点问题. 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，感染药物开发研究面临的挑战之一是如何利用不断增加的知识疾病生物学和毒性的潜在机制，沿着疾病转化和进展为MDR、XDR和PDR感染开发新的治疗策略。最大的瓶颈之一，药物的毒性是药物进入临床并最终限制临床使用的原因。当药物必须长时间使用（数月）时，这个问题变得更加严重，例如用于免疫功能低下患者的真菌感染。因此，我们集中力量，确定单个药物类别（如氨基糖苷类）的毒性途径，并解决这些问题问题从一开始。由于氨基糖苷类药物诱导的外植毛细胞损失与人类相似，我们将首先使用小鼠器官培养物进行二级筛选，以筛选无毒性的顶级化合物。我们将然后用有色豚鼠通过听性脑干反应的测定来评价听觉功能，计算感觉毛细胞损失的损失，并用血清评估最高化合物的肾功能。的结果该项目将帮助我们识别对感兴趣的微生物具有高效的新型氨基糖苷类，降低毒性。这里提出的工作，一个多学科的努力，使用快速的合成方法，抑制，和耳毒性将在本II期申请中使用体内疗效和耳毒性研究进一步开发，豚鼠模型。我们建议使用新的氨基糖苷修饰，专利NUBAD测定，小鼠豚鼠器官培养研究，以鉴定显示耳毒性降低的结合物，用于开发可以针对耐药病原体的药物，但具有更高的治疗指数。