Novel Antifungal Therapeutic Approaches

新型抗真菌治疗方法

基本信息

批准号：
8223241
负责人：
JOSEPH HEITMAN
金额：
$ 34.4万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223241
关键词：
Acquired Immunodeficiency Syndrome Amino Acids Amphotericin Amphotericin B Anabolism Animal Model Antibiotics Antifungal Agents Antifungal Therapy Aspartate Kinase Azoles Biological Biological Factors Breathing CCI-779 Calcineurin Calcineurin inhibitor Calcium Candida Candida albicans Candidate Disease Gene Candidiasis Client Combination Drug Therapy Combined Modality Therapy Complement Complex Cryptococcal Meningitis Cryptococcus neoformans Cryptococcus neoformans infection Cyclophilins Cyclosporine Drug Combinations Drug Delivery Systems Drug Formulations Drug Interactions Drug resistance Elements Enzymatic Biochemistry Enzymes Epidemic Ergosterol Exhibits Exposure to FK506 Feedback Flucytosine Fungal Meningitis Generations Genes Genetic Genetic Transcription Goals Growth Highly Active Antiretroviral Therapy Homologous Gene Human Immunosuppressive Agents Industrial fungicide Infection Injection of therapeutic agent Insecta Lipids Medical Device Metabolic Methionine Modeling Molecular Molecular Chaperones Mutation Mycoses Oropharyngeal Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Play Procedures Proteins Research Role Saccharomyces cerevisiae Signal Transduction Sirolimus Site Steroids Tacrolimus Binding Protein 1A Tail Testing Therapeutic Therapeutic Agents Threonine Translations Transplantation Veins Yeast Model System aminoacid biosynthesis analog aspartic semialdehyde base chemotherapy detection of nutrient drug development drug testing fungus gastrointestinal infection inhibitor/antagonist insight loss of function mutation mutant novel pathogen structural biology therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Fungal infections are increasing as a result of AIDS, transplantation, chemotherapy, steroids and antibiotics, and invasive procedures and medical devices. Antifungal agents were limited to amphotericin B, flucytosine, and azoles, but now the candins, second-generation azoles, and lipid based amphotericin formulations have expanded the antifungal drug armamentarium. Yet with difficulties in delivering parenteral agents, consistent efficacy, need for rapid, short courses of therapy, and emerging drug resistance, therapeutic advances remain to be achieved. Our research focuses on signaling cascades as targets for antifungal drugs. Studies are proposed on Candida albicans, the most common human fungal pathogen that remains a major mucosal pathogen in AIDS patients who fail or do not receive HAART, and Cryptococcus neoformans, the leading cause of fungal meningitis in the world due to the AIDS epidemic. Our studies have defined the mechanisms of action and targets for the antifungal immunosuppressants cyclosporin A, FK506, and rapamycin. Fungal homologs of calcineurin, cyclophilin, FKBP12, and Tor1 were identified, providing insight into biological roles and as conserved drug targets. Nonimmunosuppressive analogs that retain antifungal activity were identified. Synergistic fungicidal drug interactions were demonstrated and mechanisms of action elucidated. Calcineurin inhibition by cyclosporin A or FK506 is potently synergistic with azoles against C. albicans and of therapeutic benefit in animal models. Recent studies implicate calcineurin as an Hsp90 client protein, and Hsp90 mutations or inhibitors are also synergistic with azoles. Here we propose to define Tor, calcineurin, and FKBP12 pathways as targets for therapy. First, we will characterize Tor cascade elements and functions and target this pathway with rapamycin and less immunosuppressive rapamycin analogs (rapalogs). Second, we will elucidate relationships between Hsp90 and calcineurin and their inhibitors that render azoles fungicidal and target this pathway with novel Hsp90 inhibitors, azoles, and calcineurin inhibitors. Third, we will focus on FKBP12 control of an amino biosynthetic cascade targeted by known antifungal agents and define synergistic antifungal drug combinations. Finally, drugs, analogs, and combinations will be tested in animal models of cryptococcosis and candidiasis. Our assembled team of collaborators in natural products, medicinal chemistry, enzymology, structural biology, and animal models complements our expertise in signaling and target identification. The goal is to harness signaling cascades to develop novel antifungal therapies.

描述（由申请人提供）：由于艾滋病，移植，化学疗法，类固醇和抗生素以及侵入性程序和医疗设备，真菌感染正在增加。抗真菌剂仅限于两性霉素B，氟替辛和唑，但现在糖果，第二代叠唑和基于脂质的两性甲状腺素配方已扩大了抗真菌药物的武器armammentarium。然而，由于很难提供肠胃外药，一致的效力，快速，短暂的治疗方法以及新兴的耐药性，因此仍有待实现的治疗进展。我们的研究重点是信号级联作为抗真菌药物的靶标。提出了对白色念珠菌的研究，白色念珠菌是最常见的人类真菌病原体，在失败或不接受HAART的艾滋病患者中仍然是主要的粘膜病原体，而由于艾滋病流行病而导致世界真菌性脑膜炎的主要原因。我们的研究定义了抗真菌免疫抑制剂Cyclosporin A，FK506和雷帕霉素的作用机理和靶标。鉴定了钙调神经酶，环磷脂，FKBP12和TOR1的真菌同源物，从而洞悉了生物学作用和保守的药物靶标。鉴定了保留抗真菌活性的非免疫抑制类似物。证明了协同杀真菌药物相互作用，并阐明了作用机制。环孢菌素A或FK506抑制钙调神经磷酸酶抑制与白色念珠菌的偶氮和动物模型中的治疗益处有效。最近的研究将钙调神经酶视为HSP90客户蛋白，HSP90突变或抑制剂也与偶氮协同作用。在这里，我们建议将TOR，钙调神经酶和FKBP12途径定义为治疗的靶标。首先，我们将表征TOR级联元素和功能，并用雷帕霉素和较少免疫抑制雷帕霉素类似物（Rapalogs）靶向这一途径。其次，我们将阐明Hsp90和钙调神经酶及其抑制剂之间的关系，这些抑制剂呈现偶氮杀菌剂，并用新型的HSP90抑制剂，硫唑和钙调蛋白抑制剂靶向这一途径。第三，我们将重点关注FKBP12对已知抗真菌剂靶向的氨基生物合成级联反应的控制，并定义了协同的抗真菌药物组合。最后，将在隐球菌和念珠菌病的动物模型中测试药物，类似物和组合。我们组建的天然产品合作者团队，药物化学，酶学，结构生物学和动物模型都补充了我们在信号传导和目标识别方面的专业知识。目的是利用信号级联向开发新型抗真菌疗法。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Signaling cascades as drug targets in model and pathogenic fungi.

DOI：
发表时间：
2008-08
期刊：
Current opinion in investigational drugs
影响因子：
0
作者：
R. Bastidas;J. Reedy;Helena Morales-Johansson;J. Heitman;M. Cárdenas
通讯作者：
R. Bastidas;J. Reedy;Helena Morales-Johansson;J. Heitman;M. Cárdenas

Calcofluor white combination antifungal treatments for Trichophyton rubrum and Candida albicans.

DOI：
10.1371/journal.pone.0039405
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Kingsbury JM;Heitman J;Pinnell SR
通讯作者：
Pinnell SR

Deletion of Cryptococcus neoformans AIF ortholog promotes chromosome aneuploidy and fluconazole-resistance in a metacaspase-independent manner.

DOI：
10.1371/journal.ppat.1002364
发表时间：
2011-11
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Semighini CP;Averette AF;Perfect JR;Heitman J
通讯作者：
Heitman J

Conservation, duplication, and loss of the Tor signaling pathway in the fungal kingdom.

DOI：
10.1186/1471-2164-11-510
发表时间：
2010-09-23
期刊：
BMC genomics
影响因子：
4.4
作者：
Shertz CA;Bastidas RJ;Li W;Heitman J;Cardenas ME
通讯作者：
Cardenas ME

Pleiotropic roles of the Msi1-like protein Msl1 in Cryptococcus neoformans.

Msi1 样蛋白 Msl1 在新型隐球菌中的多效性作用。

DOI：
10.1128/ec.00261-12
发表时间：
2012
期刊：
Eukaryotic cell
影响因子：
0
作者：
Yang,Dong-Hoon;Maeng,Shinae;Strain,AnnaK;Floyd,Anna;Nielsen,Kirsten;Heitman,Joseph;Bahn,Yong-Sun
通讯作者：
Bahn,Yong-Sun