Novel antifungal therapeutics

描述(由申请人提供)：拟议研究的意义和影响。有许多与血流感染的管理有关，特别是由烟曲霉菌和念珠菌引起的感染。从文献中可以清楚地看出，部分问题与缺乏新的药物疗法有关，这些药物疗法不针对耐药菌株进行选择，也没有毒性或药物之间的相互作用。关于我们的建议，有两点令人感兴趣。首先，没有新的抗真菌药物；新药物是改良三氮唑或棘球菌素，许多仍未进行临床评估。其次，尽管与AmpB相关的问题包括毒性较低的AmpB脂质体制剂的毒性和成本增加，但这种药物仍然是非中性粒细胞减少的念珠菌血症患者的主要选择，仅次于氟康唑或棘球菌素。在这一点上，伏立康唑与氟康唑相比几乎没有优势。同样不幸的理由也被用于治疗中性粒细胞减少的患者。我们研究的影响集中在初步数据上，这些数据表明我们的化合物在几个念珠菌物种中对我们的化合物高度敏感，烟曲霉和新生念珠菌。事实上，我们化合物的最低杀菌浓度(MFC)相当于最小抑菌浓度(MIC)。这一特征在药物发现中当然很重要。最重要的是，我们的化合物对氟康唑和米卡芬净耐药的念珠菌和新生隐球菌具有抑制作用。这些新数据有力地表明，我们的化合物有一个独特的靶点(S)。此外，我们发现靶标的方法现在侧重于使用酵母基因敲除和过度表达文库进行遗传分析。其他小组的原则证明研究为我们的实验提供了信心。问题的关键是，在抗真菌药物中几乎没有选择，最近真菌疾病研究的领导人提出了开发新疗法的紧迫性。在具体目标3中，我们建议进行ADME/TOX研究，以证明我们的化合物对人类细胞具有低毒性。 公共卫生相关性：目前治疗侵袭性真菌疾病(如念珠菌病)的方法为数不多。此外，还有与用于治疗患者的抗真菌药物有关的问题。这些问题包括药物本身造成的毒性或与药物间相互作用有关的毒性。此外，三氮唑类抗真菌药物的使用导致了引起念珠菌病的念珠菌种类的变化，因为这些药物选择了更具耐药性的菌株。因此，有许多并发症与血流感染的管理有关，特别是由念珠菌引起的感染。我们研究的影响主要集中在初步数据上，这些数据表明威廉·格劳塔斯博士产生的化合物具有高敏感性和杀菌活性，他是该项目的合作伙伴。Groutas博士与Calderone博士合作，证明了先导化合物的最低杀菌浓度(MFC)与其最低抑菌浓度(MIC)相同。这一特征在药物发现中当然很重要。重要的是，HITS中体现的化学类型在结构上与目前临床和开发中使用的所有抗真菌药物不同。新的数据表明，我们的化合物抑制了20多种对氟康唑和米卡芬净耐药的光滑念珠菌、白色念珠菌和新型隐球菌，证明了与目前使用的抗真菌药物相比，它们针对的是独特的靶点。我们打算基于利用酵母基因敲除和过表达突变体库的遗传方法进行靶标鉴定。这是解决毒品目标身份问题的最直接方法。正在进行进一步的新的铅化合物鉴定，目前的提案中包括ADME/TOX研究。该计划的长期目标是通过推进1，2-苯并异噻唑啉-2(3H)-酮系列化合物在申请研究新药(IND)之前的阶段，开发具有优越特性的抗真菌感染的新疗法。

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.