Novel antifungal therapeutics

新型抗真菌疗法

• 批准号: 8142570
• 负责人: Richard Arthur Calderone
• 金额: $ 21.94万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142570
• 关键词: Allylamine; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Back; Biochemical; Biological Availability; Blood; Candida; Candida albicans; Candidiasis; Cells; Characteristics; Clinic; Collection; Cryptococcus; Cryptococcus neoformans; Data; Development; Disease; Drug Delivery Systems; Drug Interactions; Drug Kinetics; Drug resistance; Drug usage; Enzyme Inhibition; Enzymes; Exhibits; Exploratory/Developmental Grant; Expression Library; Fluconazole; Genetic; Goals; Health; Housing; Human; In Vitro; Industrial fungicide; Infection; Investigational Drugs; Investigational New Drug Application; Knock-out; Lead; Libraries; Liposomes; Literature; Liver Microsomes; Metabolic; Micafungin; Molecular Models; Molecular Target; Morbidity - disease rate; Mycoses; Oral; P-Glycoprotein; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Plague; Plasma; Plasma Proteins; Predisposition; Preparation; Property; Protein Binding; Rattus; Research; Resistance; Roentgen Rays; Screening procedure; Secure; Series; Solubility; Staging; Stream; Structure; Structure-Activity Relationship; Therapeutic; Therapeutic Intervention; Toxic effect; Triazoles; Voriconazole; Work; X-Ray Crystallography; Yeasts; aqueous; base; candidemia; chemical stability; combinatorial chemistry; cost; cytotoxicity; design; drug candidate; drug development; drug discovery; falls; foot; genetic analysis; genotoxicity; in vivo; interest; lipophilicity; molecular modeling; mortality; mutant; novel; novel therapeutics; overexpression; pre-clinical; process optimization; programs; research study; resistant strain; scaffold

DESCRIPTION (provided by applicant): Significance and impact of proposed research. There are many associated with the management of blood stream infections caused especially by A. fumigatus and Candida species. It is clear from the literature that part of the problem is associated with the lack of new drug therapies that do not select for drug-resistant strains and that are free of toxicity or drug-drug interactions. There are two points of interest in regard to our proposal. First, there are no new classes of anti- fungals; the new drugs are remodeled triazoles or echinocandins, many still not evaluated clinically. Second, in spite of the problems associated with AmpB that include toxicity and increased cost of the less toxic liposomal preparations of AmpB, this drug remains as the major fall back choice to fluconazole or an echinocandin in the non-neutropenic patient with candidemia. In this regard, voriconazole offers little advantage over fluconazole. The same unfortunate rationale is used for treating patients that are neutropenic. The impact of our studies is focused upon preliminary data that indicate high susceptibilities to our compounds among several Candida species, Aspergillus fumigatus, and C. neoformans. In fact, the minimum fungicidal concentration (MFC) of our compounds is equivalent to the minimal inhibitory concentration (MIC). This feature is certainly important in drug discovery. Of utmost importance, our compounds are inhibitory to fluconazole- and micafungin-resistant Candida species and Cryptococcus neoformans. These new data strongly show that our compounds have a unique target(s). Furthermore, our approach to target discovery now focuses upon a genetic analysis using yeast knock-out and over expression libraries. Proof-of-principle studies by other groups provide confidence for our experiments. The point is that there are few choices among anti-fungal drugs, and urgency has been suggested recently by leaders in fungal disease research to develop new treatments. We propose in specific aim 3 that ADME/TOX studies be done to demonstrate that our compounds have low toxicity to human cells. PUBLIC HEALTH RELEVANCE: Current therapies for the treatment of invasive fungal diseases such as candidiasis are few in number. Also, there are problems associated with the antifungal drugs used to treat patients. Those problems include toxicity either as a result of the drug itself or toxicity associated with drug-drug interactions. In addition, the use of triazole antifungals has resulted in a change in the spectrum of Candida species that cause candidiasis as these drugs select for more resistant strains. Thus, there are many complications associated with the management of blood stream infections caused especially by Candida species. The impact of our studies is focused upon preliminary data that indicate high susceptibilities and fungicidal activities of compounds generated by Dr. William Groutas, the Co-PI in this project. Working with Dr. Calderone, Dr. Groutas has shown that lead compounds have a minimum fungicidal concentration (MFC) that is equivalent to their minimal inhibitory concentration (MIC). This feature is certainly important in drug discovery. Importantly, the chemotype embodied in the hits is structurally distinct from all anti-fungal agents currently used in the clinic and in development. New data establish that our compounds inhibit a collection of over 20 fluconazole- and micafungin-resistant strains of C. glabrata, C. albicans, and Cryptococcus neofomans, proving that they are directed against unique targets compared to currently used anti-fungals. We intend to pursue target identification based upon genetic approaches that utilize yeast libraries of knock-out and overexpressed mutants. This is the most direct approach to solving questions about the identity of drug targets. Further new lead compound identification is in progress, and ADME/TOX studies are included in the current proposal. The long term goal of this program is the development of novel therapeutics against fungal infection with superior characteristics by advancing the 1, 2-benzisothiazolin-2(3H)-one series of compounds through the stage prior to filing for an investigational new drug (IND) application.

描述（由申请人提供）：拟研究的意义和影响。有许多与血流感染的管理有关，特别是由烟曲霉和念珠菌引起的。从文献中可以清楚地看出，部分问题与缺乏不选择耐药菌株、无毒性或药物-药物相互作用的新药物疗法有关。关于我们的建议，有两点值得注意。首先，没有新的抗真菌类；这些新药是三唑类或棘白菌素类的改型药物，许多尚未进行临床评价。其次，尽管存在与AmpB相关的问题，包括毒性和毒性较小的AmpB脂质体制剂的成本增加，但对于患有念珠菌病的非中性粒细胞减少患者，该药物仍然是氟康唑或棘白菌素的主要后备选择。在这方面，伏立康唑与氟康唑相比几乎没有优势。同样不幸的是，治疗嗜中性粒细胞减少症的病人也是如此。我们研究的影响主要集中在初步数据上，这些数据表明，我们的化合物在几种假丝酵母菌、烟曲霉和新生假丝酵母菌中具有高敏感性。事实上，我们的化合物的最低杀真菌浓度（MFC）相当于最低抑菌浓度（MIC）。这一特征在药物发现中无疑是重要的。最重要的是，我们的化合物对氟康唑和米卡芬耐药念珠菌和新型隐球菌具有抑制作用。这些新数据有力地表明，我们的化合物具有独特的靶标。此外，我们的目标发现方法现在集中在使用酵母敲除和过表达文库的遗传分析上。其他小组的原理证明研究为我们的实验提供了信心。关键是抗真菌药物的选择很少，最近真菌疾病研究的领导者已经提出开发新的治疗方法的紧迫性。我们在具体目标3中建议进行ADME/TOX研究，以证明我们的化合物对人体细胞具有低毒性。