Development of Broad Spectrum Antifungal Agents

广谱抗真菌药物的开发

• 批准号: 9909111
• 负责人: Dennis L. Wright
• 金额: $ 30万
• 依托单位: QUERCUS MOLECULAR DESIGN, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909111
• 关键词: Accounting; Affect; Aging; Antibiotics; Antifungal Agents; Antimetabolites; Area; Aspergillus fumigatus; Autoimmune Diseases; Bacteria; Biochemical; Biological Assay; Bone Marrow Transplantation; Candida; Candida albicans; Candidiasis; Cell Culture Techniques; Cells; Cessation of life; Clinical; Communicable Diseases; Computer Analysis; Cryptococcus neoformans; Data; Descriptor; Development; Development Plans; Dihydrofolate Reductase; Dihydrofolate Reductase Inhibitor; Disease; Drug resistance; Drug usage; Enzymes; Evaluation; Exhibits; Family; Fluconazole; Folic Acid; Folic Acid Antagonists; Fungal Drug Resistance; Goals; Grant; Growth; Hospitals; Human; Immunocompetent; Immunocompromised Host; Immunologics; In Vitro; Incidence; Individual; Infection; Infectious Agent; Intensive Care Units; Internal Medicine; Intestines; Laboratories; Lead; Life; Life Expectancy; Metabolic; Molecular; Multi-Drug Resistance; Mycoses; Operative Surgical Procedures; Opportunistic Infections; Oral cavity; Oral mucous membrane structure; Organ; Organism; Pathogenicity; Patients; Permeability; Persons; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Population; Positioning Attribute; Predisposition; Prevalence; Production; Property; Quercus; Resistance; Resistant candida; Route; Sepsis; Series; Skin; Small Business Technology Transfer Research; Solid; Solubility; Source; Specificity; Symptoms; Systemic infection; Testing; Therapeutic; Toxic effect; Urinary tract; Urinary tract infection; Virulence; Virulent; Work; Yeasts; active method; analog; base; candidate selection; candidemia; chemotherapy; design; drug development; drug discovery; echinocandin resistance; efficacy testing; experience; fungus; high risk; human pathogen; immunosuppressed; inhibitor/antagonist; lead candidate; lead series; mortality; novel; novel therapeutics; pathogen; pathogenic fungus; public health relevance; reproductive tract; resistant strain; screening; small molecule; targeted treatment; ward

ABSTRACT Candidiasis is a fungal infection caused by yeasts that belong to the genus Candida. Candida yeasts normally reside in the mouth, intestines and on the skin of all humans and do not pose an immediate threat to the average immunocompetent person. However, Candida can cause opportunistic and frequently life-threatening conditions in immunocompromised individuals or under conditions in which healthy bacteria levels are disrupted, especially in hospital settings. Overall, Candida spp. are responsible for roughly 10% of all blood infections with a mortality rate of 20-50%. The number of cases of invasive candidiasis is expected to rise with increased numbers of aging and immunosuppressed individuals in the population. Numerous over-the-counter agents are available for treating less severe symptoms of the skin and genital and urinary tracts; however, treatment options for systemic infections are limited by toxicity of front line therapy and increasing rates of resistance. Although C. albicans has historically been the most prominent Candida species, it is now recognized that other Candida species are increasing in prevalence with C. albicans, C. glabrata, C. tropicalis, C. parapsilosis and C. krusei considered the most virulent. The highest rates of antifungal drug resistance are associated with C. glabrata, which is intrinsically resistant to both common classes of antifungal agents, accounting for more than 70% of all echinocandin- resistant isolates and over 90% of all multidrug-resistant isolates. We have formed a new start-up venture, Quercus Molecular Design (QMD LLC), whose long-term objective is to identify, characterize, and exploit infectious disease drug targets for the treatment of the immunologically vulnerable. Since DHFR is highly conserved among fungal species, fungi-specific folate antimetabolites are anticipated to have broad spectrum activity against multiple Candida species. We hypothesize that it will be possible to develop dihydrofolate reductase (DHFR) inhibitors that inhibit multiple Candida species. This phase I proposal is based on exciting preliminary data indicating that small molecule lead compounds exhibit high levels of specificity for the fungal DHFR enzyme over the human counterpart and also exhibit excellent antifungal activity against C. albicans and C. glabrata. The purpose of this Phase 1 STTR is to determine the feasibility of developing a broadly active treatment for multiple species of Candida. To that end, efficacy of the lead series will be evaluated against isolates of Candida spp., including drug-resistant strains and the lead series will be expanded through a focused medicinal chemistry effort and tested for efficacy in vitro and in cell culture. This phase I proposal is based on a decade of work from Dr. Dennis Wright’s laboratory focused on small-molecule drug discovery in infectious disease. This proposal also leverages Dr. Lee Wright’s nearly 20 years of experience in the areas of pharmaceutical medicinal chemistry and small-molecule drug development and Dr. Michael Cynamon’s multiple decades of clinical work in the identification, evaluation and treatment of fungal disease. Our long-term goal is to develop the most promising lead compounds to create a broadly-acting Candida therapeutic.

抽象的 念珠菌是属于念珠菌属的酵母菌引起的真菌感染。念珠菌通常 居住在嘴里，肠子和所有人类的皮肤上，不会立即威胁平均 免疫能力的人。但是，念珠菌会导致机会主义和经常威胁生命的条件 在免疫功能低下的个体或健康细菌水平中断的条件下，尤其是 在医院环境中。总体而言，念珠菌属。由死亡率的所有血液感染的大约10％负责 率为20-50％。预计随着衰老数量的增加，侵入性念珠菌病的病例数量将增加 和人口中的免疫抑制个人。许多非处方药可用于 治疗皮肤的严重症状不太严重，生殖器和尿路；但是，全身治疗选择 感染受到前线治疗的毒性和抗药性增加的限制。虽然白色念珠菌有 从历史上看，历史上是最杰出的念珠菌物种，现在已经认识到其他念珠菌是 白色念珠菌，glabrata，C。tropicalis，C。parapasilosis和C. krusei的患病率增加了 最猛烈的。抗真菌药耐药性的最高速率与glabrata有关，这本质上是 对这两种常见类抗真菌剂的耐药性，占所有echinocandin-的70％以上 抗性分离株和所有抗多药抗性分离株的90％以上。我们已经成立了一个新的初创企业， Quercus分子设计（QMD LLC）的长期目标是识别，表征和利用 传染病药物靶标用于治疗免疫学脆弱性。由于DHFR高度 在真菌物种中保守的真菌特异性叶酸抗代谢物预计将具有广泛的光谱 对多种念珠菌物种的活性。我们假设可以发展二氢叶酸 抑制多种念珠菌物种的还原症（DHFR）抑制剂。我的建议基于令人兴奋的 初步数据表明，小分子铅化合物暴露于真菌的高水平特异性 在人类对应物上的DHFR酶，还表现出对白色念珠菌和 C. glabrata。该阶段1 STTR的目的是确定开发广泛活跃的可行性 用于多种念珠菌的处理。为此，将评估铅系列的效率 念珠菌属的分离株，包括耐药菌株和铅系列，将通过聚焦扩展 药物化学努力并测试了体外和细胞培养的效率。我的建议基于 丹尼斯·赖特（Dennis Wright）博士实验室的十年工作重点是传染性的小分子药物 疾病。该建议还利用了李·赖特博士在该领域的近20年经验 药物化学和小分子药物开发和迈克尔·赛南博士的多重药物 数十年来，在鉴定，评估和治疗真菌疾病方面的临床工作。我们的长期目标是 开发最有前途的铅化合物来创建广泛作用的念珠菌疗法。