Reversing Antifungal Drug Resistance

逆转抗真菌药物耐药性

• 批准号: 7694196
• 负责人: Susan L. Lindquist
• 金额: $ 2.5万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7694196
• 关键词: Address; Animal Model; Antibiotic Resistance; Antifungal Agents; Arts; Aspergillus; Aspergillus fumigatus; Azoles; Bacteria; Basic Science; Biochemical; Biological; Biological Assay; Biology; Bone Marrow Transplantation; Calcineurin; Calcineurin inhibitor; Cancer Patient; Candida; Candida albicans; Cardiovascular system; Categories; Cell Line; Cell Survival; Cells; Characteristics; Chemicals; Cherry - dietary; Client; Clinical; Clinical Trials; Collaborations; Collection; Cyclosporine; Development; Disease; Dose-Limiting; Drug Combinations; Drug Exposure; Drug resistance; Economic Burden; Economics; Engineering; Ensure; Environment; Eukaryota; Evaluation; FK506; Fever; Fluconazole; Fluconazole resistance; Funding Mechanisms; Fungal Components; Fungal Drug Resistance; Future; Generations; Genetic; Goals; Growth; Health; Healthcare Systems; High Dose Chemotherapy; Human; Immune response; Immunocompromised Host; Immunosuppressive Agents; Individual; Industrial fungicide; Infection; Institutes; Laboratories; Letters; Libraries; Life; Lung diseases; Maintenance; Malignant Neoplasms; Measures; Mediating; Molecular; Molecular Bank; Molecular Biology; Molecular Chaperones; Mutation; Mycoses; Organism; Outcome; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenocopy; Phenotype; Procedures; Production; Proteins; Publishing; Reporter; Research; Resistance; Resources; Robotics; Running; Saccharomyces cerevisiae; Screening procedure; Series; Signaling Molecule; Societies; Specificity; Stress; Structure-Activity Relationship; Systemic disease; Techniques; Technology; Testing; Therapeutic; Time; Toxic effect; United States National Institutes of Health; Work; Yeasts; analog; base; biological adaptation to stress; chaperone machinery; cost; cytotoxic; cytotoxicity; design; echinocandin resistance; follow-up; fungus; high throughput screening; human disease; human tissue; improved; inhibitor/antagonist; insight; interest; microorganism; miniaturize; novel; pathogen; public health relevance; resistance mechanism; response; therapeutic development; tissue culture

DESCRIPTION (provided by applicant): Acquired drug resistance by medically relevant microorganisms poses a grave threat to human health and has enormous economic consequences. Fungal pathogens pose a particular challenge because they are more closely related to humans than bacteria and share many of the same mechanisms at the molecular level that support the growth and survival of the cells comprising their human hosts. The number of drug classes that have distinct targets in fungi is very limited and the usefulness of current antifungal drugs is compromised owing to either significant toxicity for the patient receiving them or the frequent emergence of high grade resistance. The objective of this project is to discover new chemical compounds capable of reversing fungal drug resistance, thereby illuminating the mechanisms responsible for drug resistance in disease-causing fungi and making currently available antifungal safer and more effective. To achieve this ambitious goal, a research plan designed to achieve the following specific aims will be pursued in collaboration with a designated center within the National Institutes of Health (NIH) Molecular Libraries Probe Production Center Network (MLPCN): Aim 1: Optimize and then execute a high throughput robotic screen of hundreds of thousands of individual chemicals to find compounds that can reverse the resistance of a fungal strain that was isolated from a patient receiving the very commonly used antifungal drug fluconazole Aim 2: Evaluate the compounds identified in the primary screen by measuring their potency, their spectrum of activity against various types of fungus, their selectivity for human versus fungal cells and determine the general way in which they reverse antifungal drug resistance Aim 3: Select the 10 most promising compounds and synthesize a panel of derivatives for each one to optimize their antifungal potency and specificity. This project will combine our long established expertise in studying the molecular biology of fungi using genetic and biochemical techniques with the outstanding resources of an MLPCN center and its expertise in high throughput screening technology and medicinal chemistry. In collaboration with the Broad Institute which was recently designated an MLPCN center, the essential primary screening assay has already been developed and validated. As a result, the deliverable outcome from this brief one year project is expected to be several highly useful chemical compounds with which to probe fungal biology. These probes will be invaluable to us and others for studying the mechanisms underlying fungal drug resistance. In addition to their basic research applications, their therapeutic relevance can be readily evaluated using established animal models in future work. By virtue of the way in which they will be discovered, many of these compounds are likely to act in previously unknown and unexploited ways that could prove uniquely effective in addressing the ever increasing problem of acquired drug resistance by disease-causing microorganisms that confronts our society. PUBLIC HEALTH RELEVANCE: Acquired drug resistance by disease-causing microorganisms poses an escalating threat to human health and imposes an enormous economic burden on our health care system. This project will use state of the art screening technologies to discover chemical compounds that can reverse drug-resistance in human disease- causing fungi. By virtue of the novel way in which they will be discovered, many of these compounds are likely to act in previously unknown and unexploited ways that could prove uniquely effective in tackling the serious problem of acquired antibiotic resistance that confronts our society.

描述（由申请人提供）：医学相关微生物的获得性耐药性对人类健康构成严重威胁，并产生巨大的经济后果。真菌病原体构成了一个特殊的挑战，因为它们与人类的关系比细菌更密切，并且在分子水平上共享许多相同的机制，这些机制支持构成其人类宿主的细胞的生长和存活。在真菌中具有不同靶点的药物类别的数量非常有限，并且当前抗真菌药物的有用性由于对接受它们的患者的显著毒性或频繁出现的高级别耐药性而受到损害。该项目的目标是发现能够逆转真菌耐药性的新化合物，从而阐明致病真菌耐药性的机制，并使目前可用的抗真菌药物更安全，更有效。为了实现这一雄心勃勃的目标，将与美国国立卫生研究院（NIH）分子图书馆探针生产中心网络（MLPCN）内的指定中心合作开展旨在实现以下具体目标的研究计划：目标1：优化并执行高通量机器人筛选数十万种化学物质，以找到可以逆转真菌菌株抗性的化合物目的2：通过测量化合物的效力、它们对各种类型真菌的活性谱、它们对人细胞和真菌细胞的选择性来评价在初步筛选中鉴定的化合物，并确定它们逆转抗真菌药物抗性的一般方式目的3：选择10种最有前途的化合物，并为每种化合物合成一组衍生物，以优化其抗真菌效力和特异性。该项目将联合收割机结合我们在使用遗传和生物化学技术研究真菌分子生物学方面的长期专业知识，以及MLPCN中心在高通量筛选技术和药物化学方面的优秀资源。与最近被指定为MLPCN中心的布罗德研究所合作，已经开发并验证了基本的初步筛查试验。因此，这个简短的一年项目的可交付成果预计将是几种非常有用的化合物，用于探测真菌生物学。这些探针对于我们和其他人研究真菌耐药性的机制将是非常宝贵的。除了它们的基础研究应用，它们的治疗相关性可以很容易地在未来的工作中使用已建立的动物模型进行评估。由于它们将被发现的方式，这些化合物中的许多可能以以前未知和未开发的方式起作用，这些方式可以证明在解决我们社会面临的致病微生物日益增加的获得性耐药性问题方面具有独特的有效性。 公共卫生相关性：致病微生物的获得性耐药性对人类健康构成了不断升级的威胁，并给我们的卫生保健系统带来了巨大的经济负担。该项目将使用最先进的筛选技术来发现可以逆转人类致病真菌耐药性的化合物。由于它们将被发现的新方式，这些化合物中的许多可能以以前未知和未开发的方式发挥作用，这些方式可以证明在解决我们社会面临的获得性抗生素耐药性的严重问题方面具有独特的有效性。

项目成果

Piperazinyl quinolines as chemosensitizers to increase fluconazole susceptibility of Candida albicans clinical isolates.

• DOI: 10.1016/j.bmcl.2011.06.105
• 发表时间: 2011-09-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Youngsaye, Willmen;Vincent, Benjamin;Hartland, Cathy L.;Morgan, Barbara J.;Buhrlage, Sara J.;Johnston, Stephen;Bittker, Joshua A.;MacPherson, Lawrence;Dandapani, Sivaraman;Palmer, Michelle;Whitesell, Luke;Lindquist, Susan;Schreiber, Stuart L.;Munoz, Benito
• 通讯作者: Munoz, Benito

ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans.

• DOI: 10.3762/bjoc.9.171
• 发表时间: 2013
• 期刊: Beilstein journal of organic chemistry
• 影响因子: 2.7
• 作者: Youngsaye W;Hartland CL;Morgan BJ;Ting A;Nag PP;Vincent B;Mosher CA;Bittker JA;Dandapani S;Palmer M;Whitesell L;Lindquist S;Schreiber SL;Munoz B
• 通讯作者: Munoz B