Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Curr Pharm Des. 2011;17(13):1225-33. doi: 10.2174/138161211795703753.
The substantial morbidity and mortality associated with invasive fungal infections constitute undisputed tokens of their severity. The continued expansion of susceptible population groups (such as immunocompromised individuals, patients undergoing extensive surgery, and those hospitalized with serious underlying diseases especially in the intensive care unit) and the limitations of current antifungal agents due to toxicity issues or to the development of resistance, mandate the development of novel antifungal drugs. Currently, drug discovery is transitioning from the traditional in vitro large-scale screens of chemical libraries to more complex bioassays, including in vivo studies on whole animals; invertebrates, such as Caenorhabditis elegans, are thus gaining momentum as screening tools. Key pathogenesis features of fungal infections, including filament formation, are expressed in certain invertebrate and mammalian hosts; among the various potential hosts, C. elegans provides an attractive platform both for the study of host-pathogen interactions and the identification of new antifungal agents. Advantages of compound screening in this facile, relatively inexpensive and not as ethically challenged whole-animal context, include the simultaneous assessment of antifungal efficacy and toxicity that could result in the identification of compounds with distinct mechanisms of action, for example by promoting host immune responses or by impeding fungal virulence factors. With the recent advent of using predictive models to screen for compounds with improved chances of bioavailability in the nematode a priori, high-throughput screening of chemical libraries using the C. elegans-C. albicans antifungal discovery assay holds even greater promise for the identification of novel antifungal agents in the near future.
侵袭性真菌感染相关的高发病率和死亡率是其严重性的无可争议的标志。易感染人群的持续扩大（如免疫功能低下者、接受广泛手术的患者以及因严重基础疾病住院的患者，尤其是在重症监护病房）以及由于毒性问题或耐药性发展而导致当前抗真菌药物的局限性，都要求开发新型抗真菌药物。目前，药物发现正在从传统的大规模体外化学文库筛选向更复杂的生物测定方法转变，包括对整个动物进行体内研究；因此，秀丽隐杆线虫等无脊椎动物作为筛选工具正在得到越来越多的关注。真菌感染的关键发病特征，包括丝状形成，在某些无脊椎动物和哺乳动物宿主中表达；在各种潜在宿主中，秀丽隐杆线虫既是研究宿主-病原体相互作用的一个有吸引力的平台，也是鉴定新型抗真菌药物的一个有吸引力的平台。在这种简单、相对廉价且不存在伦理问题的整体动物环境中进行化合物筛选的优势包括同时评估抗真菌疗效和毒性，这可能导致鉴定具有不同作用机制的化合物，例如通过促进宿主免疫反应或阻碍真菌毒力因子。最近，使用预测模型来筛选在线虫中具有更高生物利用度的化合物的方法已经出现，使用秀丽隐杆线虫-白色念珠菌抗真菌发现测定法对化学文库进行高通量筛选，在不久的将来为鉴定新型抗真菌药物提供了更大的希望。
