Therapy Against Recalcitrant C. albicans Infection

针对顽固性白色念珠菌感染的治疗

• 批准号: 7999702
• 负责人: Thomas A Dahl
• 金额: $ 98.66万
• 依托单位: ARIETIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999702
• 关键词: Accounting; Acute; Affect; AlamarBlue; Amphotericin B; Animal Disease Models; Animal Model; Animal Testing; Animals; Antifungal Agents; Antifungal Therapy; Antimicrobial Resistance; Azoles; Behavior; Benchmarking; Biological Assay; Biological Availability; Caco-2 Cells; Candida; Candida albicans; Cataloging; Catalogs; Catheters; Cell Line; Cells; Chemosensitization; Clinical; Cluster Analysis; Colony-forming units; Confidence Intervals; Cream; Data; Development; Device Removal; Disease; Dose; Drug Formulations; Epithelial Cells; Esophagitis; Fibroblasts; Frequencies; Future; Gel; Gnotobiotic; Goals; Growth; HIV; Health Sciences; Hepatocyte; Human; Immune system; Immunocompromised Host; In Vitro; Industrial fungicide; Infection; Lead; Left; Lesion; Life; Local Anti-Infective Agents; Maintenance; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Metabolic; Methods; Miconazole; Microbial Biofilms; Minority; Modeling; Molecular Genetics; Multi-Drug Resistance; Mus; Mycoses; Oral; Oral candidiasis; Oryctolagus cuniculus; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Poison; Population; Predisposition; Preparation; Probability; Property; Proteins; Recurrence; Recurrent disease; Refractory; Relapse; Resistance; Resistance development; Saccharomyces cerevisiae; Saint Jude Children' s Research Hospital; Screening procedure; Series; Solutions; Structure; Structure of jugular vein; Structure-Activity Relationship; Surface; Synthesis Chemistry; System; Tennessee; Testing; Therapeutic; Therapeutic Index; Tissues; Tongue; Topical Antibiotic; Topical application; Toxic effect; Toxicity Tests; Triage; Universities; Vagina; Vaginal Douching; Vaginitis; Validation; Venous; Veterinary Medicine; Vulvovaginal Candidiasis; Woman; Work; Yeasts; absorption; analog; animal efficacy; antimicrobial; base; candida biofilm; candidemia; chemical fingerprinting; chemotherapy; comparative efficacy; cytotoxicity; design; drug development; drug discovery; drug maintenance; efficacy testing; experience; fungus; genome sequencing; high throughput screening; improved; in vivo; keratinocyte; killings; lead series; mortality; mouse model; multidisciplinary; mutant; oropharyngeal thrush; overexpression; pathogen; programs; public health relevance; scaffold; success

DESCRIPTION (provided by applicant): One of the important unresolved problems in fungal antimicrobial chemotherapy is the ineffectiveness of existing therapeutics against cells that do no exist in a rapidly-growing, planktonic population. Upon attachment to abiotic surface or tissue, C. albicans produces quiescent, drug-tolerant persister cells. Subsequent development of a biofilm protects the pathogen from the immune system. Non-growing stationary cells are also tolerant to antimicrobials. Candida biofilms are responsible for infections of catheters; our data point to involvement of persister cells in oral thrush; and relapsing vaginitis is likely due to the presence of drug-tolerant cells as well. Our in vitro studies showed that amphotericin B or miconazole applied even at high, topical concentrations are not effective against a mature biofilm of C. albicans and persister cells. The goal of this Phase II project is to develop lead compounds that potentiate conventional antifungals and are capable of eradicating all forms of the pathogen, be it exponentially growing, stationary, biofilm or persister cells. We reasoned that a compound that can interfere with the formation or maintenance of quiescent forms of infection would synergize with conventional antifungals and produce a sterilizing therapeutic. In Phase I, we developed a screen for compounds that act synergistically with antifungals and successfully identified compounds that eradicated C. albicans biofilms in vitro in the presence of miconazole. The compounds have no activity alone. This is the first observation of effective action against Candida biofilms and persister cells for any anti-fungal agent. One of the compounds, AC17, has good drug-like properties and serves as proof-of principle for developing a combination therapeutic to eradicate fungal infections. In Phase II, we will introduce a large-scale drug discovery program to identify additional attractive leads for developing potentiators of antifungals. Together with AC17, the hits from the HTS will undergo a detailed in vitro validation, medicinal chemistry optimization, and animal studies. We plan to target currently untreatable diseases: Recurrent Vulvovaginal Candidiasis (RVC), refractory Oropharyngeal Candidiasis (OPC) and biofilm infection of central venous catheters with a sterilizing combination therapeutic. Essentially 100% of women experience vaginitis due to Candida at some point in life, and the disease is treatable with azole antifungals in most cases. However, 5-8% of women suffer from relapsing vaginitis that is recalcitrant to currently available therapies. Similarly, mild cases of oropharyngeal candidiasis are usually cured with antifungal therapy, however the infection is recurrent in immunocompromised patients with HIV and cancer. C. albicans biofilm infection of central venous catheters is untreatable with currently available antifungals, requiring device removal. If left untreated, catheter biofilm infection can develop into disseminated candidemia with mortality of 38-50%. We intend to salvage biofilm- infected catheters using a lock therapy of miconazole and potentiators. This is a multidisciplinary project that brings together experts in drug development (Tom Dahl, PI); antimicrobial resistance and drug discovery (Kim Lewis, NEU); yeast molecular genetics (Carol Kumamoto, Tufts University); medicinal chemistry (Richard Lee, St. Jude Children's Research Hospital); and animal models of fungal infections (Paul Fidel, LSU; Mahmoud Ghannoum, Case Western; Saul Tzipori, Tufts). Obtaining 2 advanced leads with good efficacy in an animal model of disease will be the end-point of this Phase II project. PUBLIC HEALTH RELEVANCE: The aim of this project is to develop an effective therapeutic which will sterilize fungal infection caused by Candida albicans. Currently available therapeutics suppress, but do not sterilize the infection causing relapse and resistance. This project is based on preliminary data that describe a discovery of substances that potentiate existing antifungals and effectively eliminate the pathogen. The end result of the project will be lead therapeutics validated in an animal model of fungal infection.

描述（由申请人提供）：真菌抗菌化疗中重要的未解决的问题之一是现有疗法对细胞的无效性，而在快速增长的浮游生物种群中不存在的细胞。在附着在非生物表面或组织上时，白色念珠菌会产生静止的，耐药的持久性细胞。随后的生物膜发育可保护病原体免受免疫系统的侵害。非生长的固定细胞也耐受抗菌剂。念珠菌生物膜负责导致导管的感染；我们的数据指出，持久细胞参与口服鹅口疮；复发性阴道炎也可能是由于存在耐药细胞的存在。我们的体外研究表明，即使在高局部浓度下，两性霉素B或米其唑也无法有效，对白色念珠菌和持久细胞的成熟生物膜也无效。该II期项目的目的是开发铅化合物，以增强常规抗真菌剂，并能够消除所有形式的病原体，无论是指数增长，固定，生物膜还是持久细胞。 我们认为，一种可以干扰静止形式感染形式或维持的化合物将与常规抗真菌性抗体协同作用并产生消毒治疗。在第一阶段，我们开发了一个化合物的筛选，该化合物与抗真菌性作用协同作用，并成功地鉴定出在米诺唑存在下在体外消除白色念珠菌生物膜的化合物。这些化合物没有单独的活性。这是对念珠菌生物膜的有效作用的首次观察，并为任何抗真菌剂而言，迫使细胞。其中一种化合物AC17具有良好的药物样特性，可作为开发组合治疗的原理证明，以消除真菌感染。 在第二阶段，我们将引入一项大规模的药物发现计划，以确定开发抗真菌剂增强剂的其他有吸引力的潜在客户。与AC17一起，HTS的命中将经过详细的体外验证，药物化学优化和动物研究。 我们计划针对当前不可治疗的疾病：复发性外阴阴道念珠菌病（RVC），难治性口咽念珠菌（OPC）（OPC）和具有消毒组合治疗的中央静脉导管的生物膜感染。从本质上讲，100％的女性在生活的某个时候由于念珠菌引起的阴道炎，在大多数情况下，该疾病可以用Azole抗真菌治疗。但是，有5-8％的女性患有复发性阴道炎，这是当前可用疗法的顽固性。同样，轻度口咽念珠菌病的病例通常通过抗真菌治疗固化，但是感染在免疫功能低下的HIV和HIV和癌症患者中反复出现。中央静脉导管的白色念珠菌生物膜感染目前无法治疗，需要去除装置。如果未经治疗，导管生物膜感染可能会以38-50％的死亡率发展为传播念珠菌。我们打算使用米其唑和电剂的锁疗法来挽救生物膜感染的导管。 这是一个多学科项目，将药物开发专家汇集在一起​​（汤姆·达尔（Tom Dahl），PI）； 抗菌素耐药性和药物发现（Kim Lewis，neu）；酵母分子遗传学（塔夫茨大学Carol Kumamoto）；药物化学（Richard Lee，圣裘德儿童研究医院）；和真菌感染的动物模型（Paul Fidel，LSU； Mahmoud Ghannoum，Case Western; Saul Tzipori，Tufts）。 在疾病动物模型中获得2个具有良好功效的高级潜在客户将是该II期项目的终点。 公共卫生相关性：该项目的目的是开发一种有效的治疗性，该治疗方法将对白色念珠菌引起的真菌感染进行消毒。当前可用的治疗剂会抑制，但不要对感染进行消毒，从而导致复发和抗性。该项目基于初步数据，该数据描述了一种增强现有抗真菌性物质并有效消除病原体的物质的发现。该项目的最终结果将是在真菌感染的动物模型中验证的铅疗法。