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AIDS: Combatting drug resistance of Candida albicans

艾滋病：对抗白色念珠菌的耐药性

基本信息

批准号：
6683643
负责人：
RICHARD D CANNON
金额：
$ 13.39万
依托单位：
UNIVERSITY OF OTAGO
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-01 至 2004-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6683643
关键词：
AIDS Combatting drug resistance Candida

项目摘要

DESCRIPTION (provided by applicant): Candida albicans is a pathogenic yeast that causes serious fungal infections in the immunocompromised and opponunistic Candida infections can be the first indication of immunosuppression in HIV+ individuals. AIDS patients frequently suffer from oropharyngeal candidiasis (OPC) and require antifungal therapy. In the 1990s there was a dramatic increase in the failure of fluconazole therapy for AIDS patients with OPC due to C. albicans strains developing fluconazole resistance. The most common mechanism responsible for high level fluconazole resistance in these yeast was over-expression of drug efflux pump Cdrl p. Globally, OFC remains a major opponunistic infection in HIVIAIDS, and the widespread use of fluconazole in the third world is likely to maintain pressure on C. albicans to develop resistance. The overall objective of this research is to use a novel strategy to improve the treatment of AIDS patients with oral candidiasis by combating azoleresistance in C. albicans. Specific objectives are to: 1. Employ a novel heterologous functional hyper-expression system to determine the mechanism of pumping by Cdrl p, using both in vitro mutagenized Cdrl p and Cdrl proteins from clinical C. albicans isolates (obtained from AIDS patients) that demonstrate high and low pump activities. 2. Use the heterologous functional hyper-expression of Cdrlp to screen a unique combinatorial Doctapeptide library for peptides that inhibit the pump. This work will validate a novel approach to combating azole-resistance in C. albicana An understanding of drug pumping mechanisms may indicate new ways to circumvent efflux-mediated resistance. This project is expected to identify a lead compound with the potential to sensitize resistant strains to azole antifungals.

描述（由申请方提供）：白色念珠菌是一种致病性酵母菌，可在免疫功能低下的患者中引起严重的真菌感染，念珠菌感染可能是HIV+个体免疫抑制的第一个指征。艾滋病患者经常患有口咽念珠菌病（OPC），需要抗真菌治疗。在20世纪90年代，氟康唑治疗艾滋病患者因C.白色念珠菌菌株对氟康唑产生耐药性。在这些酵母菌中导致高水平氟康唑耐药的最常见机制是药物外排泵Cdrl p的过表达。在全球范围内，OFC仍然是HIVIIAIDS中的主要病原体感染，在第三世界广泛使用氟康唑可能会对C.白色念珠菌产生耐药性。本研究的总体目标是使用一种新的策略来改善艾滋病患者口腔念珠菌病的治疗，通过打击唑耐药的C。白色念珠菌。具体目标是： 1.采用一种新的异源功能性超表达系统，使用体外诱变的Cdrlp和来自临床的Cdrl蛋白来确定Cdrlp泵送的机制。白色念珠菌分离株（从AIDS患者获得）表现出高和低泵活性。 2.使用Cdrlp的异源功能性超表达来筛选抑制该泵的肽的独特组合Doctapeptide文库。这项工作将验证一种新的方法来打击唑类耐药的C。对药物泵送机制的理解可能提示规避外排介导的耐药性的新方法。该项目预计将确定一种具有使耐药菌株对唑类抗真菌药敏感潜力的先导化合物。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Specific interactions between the Candida albicans ABC transporter Cdr1p ectodomain and a D-octapeptide derivative inhibitor.

DOI：
10.1111/j.1365-2958.2012.08140.x
发表时间：
2012-08
期刊：
Molecular microbiology
影响因子：
3.6
作者：
Niimi K;Harding DR;Holmes AR;Lamping E;Niimi M;Tyndall JD;Cannon RD;Monk BC
通讯作者：
Monk BC

Amino acid residues affecting drug pump function in Candida albicans--C. albicans drug pump function.

影响白色念珠菌药物泵功能的氨基酸残基--C.

DOI：
10.3314/jjmm.47.275
发表时间：
2006
期刊：
Nihon Ishinkin Gakkai zasshi = Japanese journal of medical mycology
影响因子：
0
作者：
Holmes,AnnR;Tsao,Sarah;Lamping,Erwin;Niimi,Kyoko;Monk,BrianC;Tanabe,Koichi;Niimi,Masakazu;Cannon,RichardD
通讯作者：
Cannon,RichardD

Heterologous expression of Candida albicans Pma1p in Saccharomyces cerevisiae.

酿酒酵母中白色念珠菌PMA1P的异源表达。