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。

• 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
• 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

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 系统性真菌感染是艾滋病患者死亡的主要原因。这些感染很难 治疗主要是由于患者的免疫功能低下状态。此外，接受治疗的患者 经常服用多种药物，患者的日常生活之间产生相互作用的可能性很高。 药物和抗真菌治疗。我们的目标是了解药物间的相互作用如何既能改善 和复杂的系统性真菌疾病的管理。药物间相互作用可能是积极的（“协同”） - 当组合的功效大于每种药物单独的活性之和时），负 （“拮抗”-当组合功效小于每种药物单独的活性之和时），或仅 添加剂我们建议通过1）推进协同联合疗法和2）可靠的 鉴定降低治疗功效的拮抗药物相互作用。 我们完成了一个高通量筛选与唑类抗真菌药物相互作用的小分子 药物氟康唑，确定了14个协同合作伙伴和8个拮抗合作伙伴。我们将推进阿拉伯社会的 协同对作为针对三种真菌物种（新型隐球菌，念珠菌属， albicans和C. glabrata）通过1）定量真菌的脊椎动物感染模型中的改善结果 疾病，2）阐明协同相互作用的分子机制和3）计算协同相互作用的分子机制。 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。 这项工作将推进系统性，唑类耐药真菌感染的潜在治疗。我们的类比 对拮抗作用的研究将有助于预测这些相互作用，以防止有害的相互作用，并改善 为病情复杂的患者提供治疗。