A Combination Therapy Approach to Treating Drug Resistant Fungal Infections

描述（由申请人提供）：尽管引入了较新的三唑类和棘白菌素类，但侵袭性真菌感染（IFI），包括侵袭性念珠菌病（IC），仍然很难用目前可用的抗真菌药物治疗。仅在美国，每年治疗院内真菌感染的费用负担就超过26亿美元。在世界范围内，IC的年发病率约为30万。患有最常见的儿科癌症，急性白细胞白血病的儿童的死亡率约为5%;然而，如果患者发生侵袭性念珠菌病，其死亡率增加4至8倍，达到20- 40%。目前，只有三类抗真菌药物用于治疗IC，并且十三年来没有新的类别被引入市场。已经广泛认识到，解决耐药性机制并且可以与现有治疗剂组合的抗真菌治疗将提供优于当前可用治疗的巨大优势。不幸的是，与癌症化疗不同，有相对较少的治疗方案，有效地结合联合收割机不同的抗真菌剂，以实现更好的治疗效果和解决耐药性，而不增加药物毒性的负担。我们的同事Joe Heitman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磷酸酶的巨大治疗潜力。钙调神经磷酸酶抑制剂降低细胞壁应力 白色念珠菌、NCAC、烟曲霉、新型隐球菌和其他致病真菌的反应。此外，当与三唑、棘白菌素或烯丙胺组合时，钙调磷酸酶抑制剂具有高度协同作用，并且可以将MIC值降低50倍或更多。还观察到，耐药临床分离的C. albicans、A. 烟曲霉和其它真菌在体外和体内与钙调磷酸酶抑制剂组合时变得对抗真菌治疗剂敏感。然而，缺乏一种有效的，抗真菌的钙调神经抑制剂，不会导致免疫抑制，阻碍了开发这种新的目标的进展。此外，钙调磷酸酶抑制剂通常是大的、结构复杂（>700道尔顿）的分子，这阻碍了用于测试的类似物的容易产生。采用新开发的化学和结构洞察力，我们建议开发一种有效的，非免疫抑制性真菌钙调磷酸酶抑制剂，建立在我们的第一阶段项目的进展。目标1.产生密切相关的第一阶段筛选结果的类似物。目标二。在体外表征化合物以促进发展。根据需要迭代库。目标3。在体内表征化合物的药代动力学和功效。

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.