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：
7404326
负责人：
Thomas A Dahl
金额：
$ 29.96万
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 2010-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop an effective therapy against relapsing vaginosis caused by Candida albicans. The disease occurs in 8-9% of all women, and is recalcitrant to currently available therapies. Upon adherence to a surface, C. albicans forms persister cells which are tolerant to currently available antimicrobials. Known compounds alone are inactive against persisters, so we reasoned that a combination of a compound disabling persister formation with a conventional antifungal will lead to eradication of the infection. To test this hypothesis, we developed a screen for potentiators of miconazole, a standard therapy against vaginosis. A pilot screen of 5,000 compounds produced an early lead, AC9 that completely eradicates populations of C. albicans containing persisters in combination with miconazole. AC9 or miconazole alone have no activity against persisters. The Specific Aims of the project are: 1. In vitro validation of miconazole potentiators. The pilot screen of 5,000 compounds for potentiators of miconazole against C. albicans persister-producing biofilms gave 13 confirmed hits, of which 1, AC9, showed considerable microbicidal activity in combination with miconazole, but not alone. Additional hits will be obtained as described in Aim 2 below. The efficacy of potentiators in the presence of miconazole against a panel of C. albicans clinical isolates will be measured to determine MIC90 of the compound. Toxicity against human cells will be also examined. The probability of resistance development to the compound in the presence of miconazole will additionally be determined. Milestone: complete in vitro validation of AC9 and other lead compounds, which will indicate the feasibility of advancing these leads into animal studies at Phase II. 2. Identifying additional miconazole potentiators. a. Analogs of hit compounds. We will identify chemical analogs of AC9 and test them for potentiation of miconazole. Any compound with activity superior to AC9 will enter into validation. b. Screening for additional lead compounds. A compound library will be screened in a high-throughput format. As hits are identified, they, together with their available analogs, will enter the validation process described in Aim 1. Milestone: Identify ~10 potentiators of miconazole capable of eradicating a C. albicans biofilm and complete their in vitro validation. The proposed study will form the basis of a subsequent Phase II project, aimed at in vivo validation of the leads and their medicinal chemistry optimization. C. albicans is the major human fungal pathogen that forms essentially untreatable biofilm infections. This includes relapsing fungal vaginosis which afflicts 8-9% of all women and is recalcitrant to current therapies. This project will develop lead compounds that will form the basis for an effective therapeutic against vaginosis.

描述（由申请人提供）：该项目的长期目标是开发一种针对白色念珠菌引起的复发性阴道病的有效疗法。 8-9% 的女性患有这种疾病，并且目前可用的治疗方法难以奏效。粘附到表面后，白色念珠菌会形成对当前可用的抗菌剂具有耐受性的持续细胞。单独的已知化合物对持久菌没有活性，因此我们推断，将抑制持久菌形成的化合物与常规抗真菌药物组合使用将能够根除感染。为了检验这一假设，我们开发了一种咪康唑增效剂的筛选方法，咪康唑是一种针对阴道病的标准疗法。对 5,000 种化合物进行的中试筛选产生了一种早期先导化合物 AC9，与咪康唑联用可完全根除含有持续存在的白色念珠菌种群。 AC9 或咪康唑单独对持续者没有活性。该项目的具体目标是： 1. 咪康唑增效剂的体外验证。对 5,000 种咪康唑增效剂化合物进行了初步筛选，结果显示 13 种已确认有效，其中 1 种 AC9 与咪康唑联合使用具有相当大的杀菌活性，但单独使用时效果不佳。将按照下面的目标 2 中的描述获得额外的命中。将测量增效剂在咪康唑存在下对一组白色念珠菌临床分离株的功效以确定该化合物的 MIC90。还将检查对人体细胞的毒性。另外，还将确定在咪康唑存在下对该化合物产生耐药性的可能性。里程碑：完成 AC9 和其他先导化合物的体外验证，这将表明将这些先导化合物推进到 II 期动物研究的可行性。 2. 识别其他咪康唑增效剂。一个。热门化合物的类似物。我们将鉴定 AC9 的化学类似物并测试它们对咪康唑的增强作用。任何活性优于 AC9 的化合物都将进入验证阶段。 b.筛选其他先导化合物。将以高通量形式筛选化合物库。当鉴定出命中后，它们及其可用的类似物将进入目标 1 中描述的验证过程。里程碑：鉴定出约 10 种能够根除白色念珠菌生物膜的咪康唑增效剂，并完成其体外验证。拟议的研究将构成后续二期项目的基础，旨在对先导化合物进行体内验证及其药物化学优化。白色念珠菌是主要的人类真菌病原体，可形成基本上无法治疗的生物膜感染。其中包括复发性真菌性阴道病，该病困扰着 8-9% 的女性，并且对当前的治疗方法无效。该项目将开发先导化合物，为有效治疗阴道病奠定基础。