Exploiting synergistic and antagonistic interactions with antifungal drugs to improve disease treatment.

利用与抗真菌药物的协同和拮抗相互作用来改善疾病治疗。

基本信息

批准号：
10456329
负责人：
JESSICA Conrad BROWN
金额：
$ 38.13万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-08 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456329
关键词：
Acquired Immunodeficiency Syndrome Adopted Amphotericin B Antifungal Agents Antifungal Therapy Azole resistance Azoles Blood Circulation Candida albicans Cause of Death Cells Cessation of life Clinical Clinical Trials Combined Modality Therapy Complex Cryptococcal Meningitis Cryptococcus Cryptococcus neoformans Development Disease Disease Outcome Drug Combinations Drug Interactions FDA approved Fluconazole Flucytosine Fungal Meningitis Genes Goals Growth Guidelines Health Immunocompromised Host Individual Industrial fungicide Infection Infectious Agent Meningitis Modeling Molecular Mycoses Organism Outcome Pathway interactions Patient Care Patients Pharmaceutical Preparations Preclinical Testing Resistance Series Structure Sum Treatment Efficacy Work Zebrafish antagonist clinical practice drug repurposing efficacy evaluation experimental study fungus high throughput screening improved microbial mortality mouse model mutant pathogen pathogenic fungus prevent small molecule standard of care treatment duration

项目摘要

Project summary Systemic fungal infections are a primary cause of death for AIDS patients. These infections are difficult to treat due primarily to patients’ immunocompromised state. Moreover, patients receiving treatment are frequently taking multiple medications, creating a high potential for interactions between patients’ routine medication and antifungal therapies. Our goal is to understand how drug-drug interactions can both improve and complicate management of systemic fungal diseases. Drug-drug interactions can be positive (“synergistic” – when the efficacy of the combination is greater than the sum of each drug’s activity alone), negative (“antagonistic” – when the combined efficacy is less than the sum of each drug’s activity alone), or merely additive. We propose to improve treatment by 1) advancing synergistic combination therapies and 2) reliable identification of antagonistic drug interactions that decrease treatment efficacy. We completed a high-throughput screen for small molecules that interact with the azole class antifungal drug fluconazole, identifying 14 synergistic partners and 8 antagonistic partners. We will advance the synergistic pairs as potential treatments against three fungal species (Cryptococcus neoformans, Candida albicans, and C. glabrata) by 1) quantitating improvement outcomes in vertebrate infection model of fungal disease, 2) elucidating the molecular mechanisms underlying synergistic interactions and 3) calculating the potential clinical impact of antagonistic interactions and determining if they are widespread within drug classes. This work will advance potential treatments for systemic, azole-resistant fungal infections. Our analogous studies on antagonism will facilitate prediction of these interactions to prevent harmful interactions and improve treatments for patients with complex conditions.

项目摘要全身真菌感染是艾滋病患者死亡的主要原因。这些感染很困难主要是由于患者免疫功能低下的状态而治疗的。而且，接受治疗的患者是经常服用多种药物，为患者常规之间的相互作用带来很高的潜力药物和抗真菌疗法。我们的目标是了解药物互动如何可以改善以及全身真菌疾病的紧凑管理。药物互动可以是积极的（“协同作用” - 当组合的效率大于仅每种药物活性的总和时）（“拮抗” - 当组合效率仅小于每种药物活动的总和时）或仅仅添加剂。我们建议通过1）提高协同组合疗法和2）可靠鉴定降低治疗效率的拮抗药物相互作用。我们完成了与Azole类抗真菌相互作用的小分子的高通量屏幕药物氟康唑，确定14个协同伴侣和8个对抗伴侣。我们将推进协同对作为针对三种真菌物种的潜在治疗方法（Neoformans，念珠菌白色念珠菌和C. glabrata）通过1）定量真菌脊椎动物感染模型的改善结果疾病，2）阐明协同相互作用的分子机制，3）计算拮抗相互作用的潜在临床影响，并确定它们是否在药物类别中广泛存在。这项工作将推动针对全身性，抗唑的真菌感染的潜在治疗方法。我们的类似拮抗作用的研究将促进这些相互作用的预测，以防止有害相互作用并改善对具有复杂条件的患者的治疗。