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Broad spectrum antifungals targeting fatty acid biosynthesis

针对脂肪酸生物合成的广谱抗真菌药

基本信息

批准号：
10392323
负责人：
Glen Palmer
金额：
$ 47.8万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-08 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10392323
关键词：
Affect Anti-Bacterial Agents Antifungal Agents Antifungal Therapy Aspergillus fumigatus Bacteria Biochemical Biological Assay Biological Products Candida albicans Cause of Death Cells Chemical Agents Chemicals Clinical Constitution Cryptococcus neoformans Development Diabetes Mellitus Drug Kinetics Enzymes Fatty Acid Desaturases Fatty Acids Fatty-acid synthase Generations Growth Human In Vitro Incidence Individual Laboratories Lead Libraries Life Lipids Malignant Neoplasms Mammalian Cell Metabolic syndrome Metabolism Methods Monitor Mucous Membrane Mycoses Natural Products Obesity Pathogenicity Pathway interactions Patient-Focused Outcomes Patients Persons Pharmaceutical Preparations Phase Physiological Population Prevalence Process Property Proteins Refractory Resistance Structure-Activity Relationship Testing Therapeutic Toxic effect Toxicology Treatment Efficacy Triclosan base efficacy testing fatty acid biosynthesis fitness fungus high throughput screening human disease human pathogen improved in vivo in vivo evaluation inhibitor innovation interest isoniazid mortality mouse model novel therapeutics pathogenic fungus protein expression screening small molecule subcutaneous synthetic enzyme targeted treatment

项目摘要

An estimated 1.5 million people die each year from invasive fungal infections, and many millions more are afflicted by debilitating mucosal and subcutaneous mycoses. Current antifungal therapies have serious deficiencies including poor efficacy, limited spectrum of activity, patient toxicity and the emergence of resistant fungi. Consequently, mortality rates have remained disturbingly high. New and improved therapeutic options are desperately needed to improve patient outcomes and redress the rise of resistance. Yet the discovery and development of new pharmocotherapies remains a frustratingly inefficient process. The objective of phase 1 (R21) of this proposal is to apply an unconventional chemical screening strategy to identify physiologically active, and fungal selective inhibitors of fatty acid (FA) biosynthesis. Our approach will focus upon fatty acid synthase (FAS) and the Ole1p FA desaturase, both of which have a fundamentally different structural organization and functional constitution compared to their mammalian counterparts. FAS and Ole1p are both essential for the viability of infectious fungi in vivo, including the prevalent human pathogens Candida albicans and Cryptococcus neoformans. We propose to exploit these targets to develop a new class of efficacious and broad spectrum antifungal therapy. A new whole-cell based approach developed within our lab termed Target Abundance based Fitness Screening (TAFiS), will be applied to identify specific inhibitors of C. albicans FAS and Ole1p. This method facilitates the selection of chemical probes that interact with a specific target protein within intact cells, thereby combining the advantages of traditional target- and cell- based screens into a single high-throughput assay. Inhibition of FA synthesis will be confirmed through biochemical analysis of treated fungal and mammalian cells, and those with fungal selective activity identified. In phase 2 (R33), the antifungal potency, selectivity and ADME properties of lead compounds will be optimized, and structure-activity relationships established. The spectrum of activity of selected leads will also be tested against important human fungal pathogens, and to isolates resistant to current antifungal drugs. Finally, the biopharmaceutic, pharmacokinetic and toxicologic properties of selected leads will be assessed before antifungal efficacy is tested in a mouse model of disseminated fungal infection. Completion of this study will facilitate the development of a new generation of antifungal drugs that can cure invasive fungal infections that are refractory to current treatment options.

据估计，每年有150万人死于侵袭性真菌感染，还有数百万人患有衰弱的粘膜和皮下真菌病。目前的抗真菌疗法有严重的不足之处包括疗效差、活性范围有限、患者毒性和出现耐药性真菌。因此，死亡率一直居高不下，令人不安。新的和改进的治疗方案是改善患者预后和纠正抵抗力上升的迫切需要。然而，这一发现和开发新的药物疗法仍然是一个令人沮丧的低效过程。第一阶段的目标 (R21)这项提议的目的是应用一种非常规的化学筛查策略来识别生理上的脂肪酸(FA)生物合成的活性和真菌选择性抑制剂。我们的方法将集中在脂肪酸上合成酶(FAS)和Ole1p脂肪酸去饱和酶，两者具有根本不同的结构与它们的哺乳动物同类相比，它们的组织和功能构成。Fas和Ole1p都是对体内感染真菌的生存至关重要，包括流行的人类病原体白色念珠菌和新生隐球菌。我们建议利用这些目标来开发一类新的有效和广谱抗真菌疗法。在我们实验室内开发的一种新的基于全细胞的方法，称为Target 基于丰度的适合性筛选(TAFIS)将用于鉴定白念珠菌Fas的特异性抑制物和Ole1p。这种方法便于选择与特定目标蛋白相互作用的化学探针在完整的细胞内，从而将传统的基于目标的筛选和基于细胞的筛选的优点结合到单个高通量分析。抑制FA合成将通过处理后的生化分析来确认真菌和哺乳动物细胞，以及那些具有真菌选择性活性的细胞。在第2阶段(R33)，抗真菌药物先导化合物的效力、选择性和ADME性质将得到优化，结构-活性建立了关系。选定的铅的活性光谱也将针对重要的人类真菌病原体，以及对当前抗真菌药物耐药的菌株。最后，生物制药，将评估选定的先导化合物的药代动力学和毒理学特性，然后再进行抗真菌疗效在播散性真菌感染的小鼠模型上进行了测试。这项研究完成后，将有助开发可治愈难治性侵袭性真菌感染的新一代抗真菌药物到目前的治疗方案。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Titration of C-5 Sterol Desaturase Activity Reveals Its Relationship to Candida albicans Virulence and Antifungal Susceptibility Is Dependent upon Host Immune Status.

DOI：
10.1128/mbio.00115-22
发表时间：
2022-04-26
期刊：
MBIO
影响因子：
6.4
作者：
Regan, Jessica;DeJarnette, Christian;Luna-Tapia, Arturo;Parker, Josie E.;Reitler, Parker;Barnett, Stacey;Tucker, Katie M.;Kelly, Steven L.;Palmer, Glen E.
通讯作者：
Palmer, Glen E.

Target Abundance-Based Fitness Screening (TAFiS) Facilitates Rapid Identification of Target-Specific and Physiologically Active Chemical Probes.

DOI：
10.1128/msphere.00379-17
发表时间：
2017-09
期刊：
mSphere
影响因子：
4.8
作者：
Butts A;DeJarnette C;Peters TL;Parker JE;Kerns ME;Eberle KE;Kelly SL;Palmer GE
通讯作者：
Palmer GE

Titrating Gene Function in the Human Fungal Pathogen Candida albicans through Poly-Adenosine Tract Insertion.

通过多聚腺苷束插入滴定人类真菌病原体白色念珠菌的基因功能。