Treatment and Prevention of Systemic Candidiasis

系统性念珠菌病的治疗和预防

• 批准号: 9813830
• 负责人: SUZANNE M NOBLE
• 金额: $ 48.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-09 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813830
• 关键词: Affect; Amphotericin; Animal Disease Models; Animal Model; Animals; Antibiotics; Antifungal Agents; Antifungal Antibiotics; Azoles; Biological Assay; Blood Circulation; Candida; Candida albicans; Candidiasis; Catheters; Cellulitis; Cessation of life; Characteristics; Clinical; Collection; Complex; Cyclophosphamide; Data; Defect; Disease; Disseminated candidiasis; Doxycycline; Drug Interactions; Drug Targeting; Drug or chemical Tissue Distribution; Drug resistance; Epithelial; Exposure to; Follow-Up Studies; Genes; Genetic; Gut Mucosa; High-Throughput Nucleotide Sequencing; Histology; Hospital Mortality; Human Microbiome; Immunosuppressive Agents; Individual; Infection; Infectious Skin Diseases; Injections; Intravenous; Investigation; Laboratories; Methods; Modeling; Mucositis; Mucous Membrane; Mus; Natural History; Nature; Neutropenia; Organ; Outcome; Parenteral Nutrition; Patients; Pharmaceutical Preparations; Phase; Phenotype; Population; Prevention; Publishing; Recovery; Risk Factors; Sepsis; Skin; Sterility; Structure of jugular vein; Surface; Symbiosis; System; Tail; Testing; Therapeutic Intervention; Time; Toxic effect; Veins; Virulence; Work; Yeasts; animal model development; base; candidemia; chemotherapeutic agent; clinically relevant; cytotoxic; drug candidate; drug development; fitness; gastrointestinal; gut microbiota; improved; in vivo; innovation; insight; intravenous injection; mortality; mouse model; mutant; novel; pathogen; pathogenic microbe; urogenital tract

ABSTRACT Objective: We propose an innovative approach towards the discovery of new targets for anti-Candida drug development. Our approach is based on the concept that, although invasive C. albicans infections typically originate from commensal populations populating the host gut mucosa and skin, the critical transition from superficial to invasive infection is absent from the standard intravenous injection model of virulence. Therefore, we will develop improved animal models that better represent the natural history of disseminated candidiasis and to exploit the new systems to identify much-needed antifungal drug targets. Rationale: Candida albicans is a yeast component of the human microbiome that persists stably on mucocutaneous surfaces of the gut, skin, and genitourinary tract for the lifetime of the host. It is also a pathogen that causes highly morbid invasive infections in patients with certain risk factors, such as exposure to antibiotics, immunosuppressants, parenteral nutrition, or intravenous catheters. Candida spp. are the fourth most common cause of bloodstream infections in US hospitals, and mortality from candidemia remains high at ~40%. The most important therapeutic intervention in treatment of bloodstream candidiasis is the early initiation of antifungal antibiotics, such that mortality increases with each day that appropriate therapy is delayed. Unfortunately, our antifungal armamentarium is currently limited to only a handful of drugs. Moreover, the choice of drugs in debilitated patients is often further limited by significant toxicities (e.g. amphotericin, azoles), restricted tissue distribution (e.g. echinocandins), and complex drug-drug interactions (e.g. azoles). These issues and the emergence of drug resistance in selected clinical isolates have created an urgent need for additional, potent, safe antifungal drugs. Unlike many microbial pathogens, C. albicans infections typically originate from the commensal population, when yeasts on the skin or in the gut manage to penetrate through epithelial barriers. We propose that the specific pathogen functions required for this transition have been missed by current methods for investigating virulence. To test this hypothesis, we have initiated development of animal models of invasive candidiasis that include 1) the transition from localized skin infection (cellulitis) to bloodstream infection and 2) invasion of gut commensals through the gastrointestinal mucosa to surrounding organs. We propose to exploit these models to screen C. albicans mutant collections for functions required for disseminated disease. Our functional screens and focused follow up studies will identify novel targets for the prevention and treatment of invasive candidiasis.

摘要 目的：为寻找抗念珠菌药物的新靶点提供新的思路 发展我们的方法是基于这样的概念，虽然侵入性C。白色念珠菌感染通常 起源于宿主肠道粘膜和皮肤的寄生虫种群， 标准的静脉注射毒力模型中不存在浅表至侵入性感染。因此，我们认为， 我们将开发更好的动物模型，以更好地代表播散性念珠菌病的自然史。 并利用新系统来确定急需的抗真菌药物靶标。 依据：白色念珠菌是人体微生物组的酵母菌组分， 肠道、皮肤和泌尿生殖道的粘膜皮肤表面。也是一 在具有某些风险因素的患者中引起高度病态侵入性感染的病原体，例如暴露于 抗生素、免疫抑制剂、胃肠外营养或静脉导管。念珠菌是第四 念珠菌血症是美国医院血液感染的最常见原因， ~ 40%。治疗血流念珠菌病最重要的治疗干预是早期 开始使用抗真菌抗生素，这样，死亡率随着适当治疗的每一天而增加， 耽搁了不幸的是，我们的抗真菌药物目前仅限于少数药物。 此外，虚弱患者的药物选择通常进一步受到显著毒性的限制（例如， 阿替霉素、唑类）、组织分布受限（例如棘白菌素）和复杂的药物相互作用 (e.g.唑类）。这些问题和选定的临床分离株中出现的耐药性已经产生了一种新的耐药性。 迫切需要额外的，有效的，安全的抗真菌药物。与许多微生物病原体不同，C.白色 感染通常起源于皮肤上或肠道中的酵母菌， 穿透上皮屏障我们认为，这种特殊的病原体功能需要 目前研究毒力的方法错过了这种转变。为了验证这个假设，我们有 发起了侵袭性念珠菌病动物模型的开发，包括1）从局部皮肤 感染（蜂窝织炎）到血流感染和2）通过胃肠道侵入肠道 粘膜到周围器官。我们建议利用这些模型来筛选C。白色念珠菌突变体集合 传播性疾病所需的功能。我们的功能筛查和重点随访研究将 确定预防和治疗侵袭性念珠菌病的新靶点。