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 念珠菌病是由念珠菌属酵母菌引起的真菌感染。 存在于所有人的口腔、肠道和皮肤上，不会对普通人构成直接威胁 然而，念珠菌可能会导致机会性且经常危及生命的疾病。 在免疫功能低下的个体中或在健康细菌水平被破坏的条件下，尤其是 总体而言，念珠菌属导致约 10% 的血液感染死亡。 预计侵袭性念珠菌病的发病率会随着老龄化人数的增加而增加。 人群中的免疫抑制个体可以使用许多非处方药。 治疗不太严重的皮肤、生殖器和泌尿道症状；然而，全身治疗选择； 尽管白色念珠菌具有一线治疗的毒性和耐药率的增加，但感染仍受到限制。 历史上是最著名的念珠菌属物种，现在人们认识到其他念珠菌属物种 白色念珠菌、光滑念珠菌、热带念珠菌、近平滑念珠菌和克柔念珠菌的流行率增加被认为是 抗真菌药物耐药率最高的是光滑念珠菌，其本质上是致命的。 对两种常见抗真菌药物均具有耐药性，占所有棘白菌素的 70% 以上 耐药菌株和超过 90% 的多重耐药菌株我们已经成立了一家新的初创企业， Quercus Molecular Design (QMD LLC)，其长期目标是识别、表征和利用 由于 DHFR 高度高，因此成为治疗免疫脆弱者的传染病药物靶标。 在真菌物种中保守，真菌特异性叶酸抗代谢物预计具有广谱 我们发现开发二氢叶酸是可能的。 抑制多种念珠菌的还原酶 (DHFR) 抑制剂 这一阶段的提案基于令人兴奋的基础。 初步数据表明小分子先导化合物对真菌表现出高水平的特异性 DHFR 酶优于人类对应物，并且还对白色念珠菌和念珠菌表现出优异的抗真菌活性 第一阶段 STTR 的目的是确定开发广泛活跃的 C. glabrata 的可行性。 为此，将针对多种念珠菌的治疗效果进行评估。 念珠菌属的分离株，包括耐药菌株和先导系列将通过有针对性的扩大 该第一阶段提案基于药物化学工作并在体外和细胞培养中进行了功效测试。 Dennis Wright 博士实验室十年来专注于感染性小分子药物发现 该提案还利用了 Lee Wright 博士在以下领域近 20 年的经验。 药物药物化学和小分子药物开发以及 Michael Cynamon 博士的多项研究 几十年来在真菌病的鉴定、评估和治疗方面的临床工作是我们的长期目标。 开发最有前途的先导化合物，以创造一种广泛作用的念珠菌治疗剂。