A Combination Therapy Approach to Treating Drug Resistant Fungal Infections

描述(申请人提供)：尽管引入了新的三氮唑和棘球菌素类药物，但侵袭性真菌感染(IFI)，包括侵袭性念珠菌病(IC)，仍然很难用现有的抗真菌药物治疗。仅在美国，治疗医院真菌感染的年成本负担就超过26亿美元。在世界范围内，IC的年发病率约为30万。儿童患有最常见的癌症--急性白血病，死亡率约为5%；然而，如果患者发展为侵袭性念珠菌病，他们的死亡率将增加4-8倍，达到20-40%。目前，仅有三类抗真菌药物用于治疗IC，13年来没有新的一类药物进入市场。人们普遍认为，针对耐药机制并可与现有治疗药物相结合的抗真菌治疗将比目前可用的治疗方法提供巨大的优势。不幸的是，与癌症化疗不同的是，相对较少的治疗方案能够有效地结合不同的抗真菌药物来实现更好的治疗结果，并在不增加药物毒性负担的情况下解决耐药性问题。我们的同事乔·海特曼教授和其他人在实验室进行的工作揭示了抑制真菌蛋白钙调神经磷酸酶的巨大治疗潜力。钙调神经磷酸酶抑制细胞壁应力 白色念珠菌、NCAC、烟曲霉、新生隐球菌和其他致病真菌的反应。此外，当与三氮唑、棘球蛋白或烯丙胺结合时，钙调神经磷酸酶抑制剂具有高度的协同作用，可以将MIC值降低50倍或更多。临床分离的白色念珠菌耐药株、A。 在体外和体内，当与钙调神经磷酸酶抑制剂结合时，烟曲霉菌和其他真菌对抗真菌治疗变得敏感。然而，缺乏一种有效的、不会导致免疫抑制的抗真菌钙调神经磷酸酶抑制剂阻碍了开发这一新靶点的进展。此外，钙调神经磷酸酶抑制剂通常是大的、结构复杂的(&gt；700道尔顿)分子，这阻碍了轻松地创建用于测试的类似物。利用新开发的化学和结构洞察力，我们建议在我们第一阶段项目进展的基础上，开发一种有效的、非免疫抑制的真菌钙调神经磷酸酶抑制剂。目的1.从第一阶段的筛选中产生与命中结果密切相关的类似物。目的2.体外表征化合物以促进进展。根据需要迭代库。目的3.研究化合物在体内的药代动力学和药效。

DESCRIPTION (provided by applicant): Despite the introduction of newer triazoles and echinocandins, invasive fungal infections (IFI's) including invasive candidiasis (IC) remain very difficult to treat with currently available antifungals. The annual cost burden of treating nosocomial fungal infections exceeds $2.6 billion a year in the United States alone. Worldwide, the annual incidence of IC is about 300,000. Children suffering from the most common pediatric cancer, acute leukocytic leukemia have an approximate 5% mortality rate; however, if the patient develops invasive candidiasis, their mortality rate increases 4 to 8 times to 20-40%. Currently, only three classes of antifungal drugs are employed to treat IC, and no new class has been introduced to the market for thirteen years. It has been widely recognized that antifungal treatments which address mechanisms of drug resistance and could be combined with existing therapeutics would provide a tremendous advantage over currently available treatments. Unfortunately, unlike cancer chemotherapy, there are relatively few treatment regimens that productively combine different antifungals to achieve better therapeutic outcomes and address drug resistance without the added burden of drug toxicity. Work performed in the lab of our colleague, Prof. Joe Heitman and others has revealed the tremendous therapeutic potential of inhibiting the fungal protein, calcineurin. Calcineurin inhibition compromises the cell wall stress response of Candida albicans, NCAC's, Aspergillus fumigatus, Cryptococcus neoformans, and other pathogenic fungi. Furthermore, when combined with triazoles, echinocandins, or allylamines, calcineurin inhibitors are highly synergistic and can reduce the MIC value by a factor of 50 or more. It has also been observed that resistant clinical isolates of C. albicans, A. fumigatus, and other fungi become susceptible to antifungal therapeutics when combined with a calcineurin inhibitor both in vitro and in vivo. However, the lack of a potent, antifungal calcineuin inhibitor that does not cause immunosuppression has hindered progress in exploiting this novel target. Moreover, calcineurin inhibitors are typically are large, structurally complex (>700 Daltons) molecules and this has hindered the facile creation of analogues for testing. Employing newly developed chemistry and structural insight, we propose developing a potent, non-immunosuppressive fungal calcineurin inhibitor, building on progress from our Phase I project. Aim 1. Generate closely related analogs of hits resulting from screens from Phase I. Aim 2. Characterize compounds in vitro for advancement. Iterate library as required. Aim 3. Characterize compounds in vivo for pharmacokinetics and efficacy.