Therapy Against Recalcitrant C. albicans Infection

针对顽固性白色念珠菌感染的治疗

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：真菌抗微生物化疗中尚未解决的重要问题之一是现有疗法对快速增长的浮游种群中不存在的细胞无效。白色念珠菌附着在非生物表面或组织上后，会产生静止的、耐药的持久细胞。随后形成的生物膜可以保护病原体免受免疫系统的侵害。非生长的静止细胞也对抗菌药物具有耐受性。念珠菌生物膜导致导管感染；我们的数据表明鹅口疮中存在存留细胞的参与；复发性阴道炎也可能是由于耐药细胞的存在造成的。我们的体外研究表明，即使局部使用高浓度的两性霉素 B 或咪康唑，也不能有效对抗白色念珠菌和持续细胞的成熟生物膜。该二期项目的目标是开发先导化合物，增强传统抗真菌药物的作用，并能够根除所有形式的病原体，无论是呈指数增长的、静止的、生物膜的还是持续存在的细胞。我们推断，一种可以干扰静止形式感染的形成或维持的化合物将与传统抗真菌药物协同作用并产生灭菌治疗剂。在第一阶段，我们开发了一种与抗真菌药物协同作用的化合物筛选方法，并成功鉴定出在咪康唑存在的情况下能够在体外根除白色念珠菌生物膜的化合物。这些化合物单独没有活性。这是任何抗真菌剂对念珠菌生物膜和持久细胞有效作用的首次观察。其中一种化合物 AC17 具有良好的药物样特性，可作为开发根除真菌感染的联合疗法的原理证明。在第二阶段，我们将引入一项大规模的药物发现计划，以确定用于开发抗真菌药物增效剂的其他有吸引力的先导化合物。 HTS 的命中产品将与 AC17 一起进行详细的体外验证、药物化学优化和动物研究。我们计划针对目前无法治疗的疾病：复发性外阴阴道念珠菌病 (RVC)、难治性口咽念珠菌病 (OPC) 和中央静脉导管生物膜感染，采用消毒组合疗法。基本上 100% 的女性在一生中的某个阶段都会经历由念珠菌引起的阴道炎，并且在大多数情况下，这种疾病可以用唑类抗真菌药物治疗。然而，5-8% 的女性患有复发性阴道炎，目前可用的治疗方法难以奏效。同样，轻度口咽念珠菌病通常可以通过抗真菌治疗治愈，但在免疫功能低下的艾滋病毒和癌症患者中，感染会复发。目前可用的抗真菌药物无法治疗中心静脉导管的白色念珠菌生物膜感染，需要移除装置。如果不及时治疗，导管生物膜感染可发展为播散性念珠菌血症，死亡率为 38-50%。我们打算使用咪康唑和增效剂的封闭疗法来挽救生物膜感染的导管。这是一个多学科项目，汇集了药物开发专家（Tom Dahl，PI）；抗菌素耐药性和药物发现（Kim Lewis，NEU）；酵母分子遗传学（Carol Kumamoto，塔夫茨大学）；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，路易斯安那州立大学；Mahmoud Ghannoum，Case Western；Saul Tzipori，塔夫茨大学）。在疾病动物模型中获得两条具有良好疗效的先进线索将是该二期项目的终点。公共健康相关性：该项目的目的是开发一种有效的治疗方法，可以消除白色念珠菌引起的真菌感染。目前可用的治疗方法可以抑制但不能消除导致复发和耐药的感染。该项目基于初步数据，这些数据描述了一种增强现有抗真菌药物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动物模型中验证主要疗法。