Giardia duodenalis, the most prevalent human intestinal parasite causes the disease, giardiasis. On an annual basis G. duodenalis infects ~1 billion people, of which ~280 million develop symptomatic disease. Giardiasis can be severe and chronic, causing malnutrition, stunted growth and poor cognitive development in children. Current treatment options rely on drugs with declining efficacy and side-effects. To improve the health and well-being of millions of people world-wide, new anti-Giardia drugs with different modes of action to currently used drugs are required. The Medicines for Malaria Venture's Pathogen Box, a collection of bio-active compounds specifically chosen to stimulate infectious disease drug discovery, represents an opportunity for the discovery of new anti-Giardia agents. While the anti-Giardia activity of Pathogen Box compounds has been reported, this work failed to identify known anti-Giardia controls within the compound set. It also reported the activity of compounds previously screened and shown to be inactive by others, suggesting data may be inaccurate. Given these concerns the anti-Giardia activity of Pathogen Box compounds was re-assessed in the current study. Data from this work identified thirteen compounds with anti-Giardia IC50 values ≤2 μM. Five of these compounds were reference compounds (marketed drugs with known anti-microbial activity), or analogues of compounds with previously described anti-Giardia activity. However, eight, including MMV676358 and MMV028694, which demonstrated potent sub-μM IC50s against assemblage A, B and metronidazole resistant parasites (0.3 μM and 0.9 μM respectively), may represent new leads for future drug development. Interestingly, only four of these compounds were identified in the previously reported Pathogen Box screen highlighting the importance of assay selection and design when assessing compounds for activity against infectious agents.

中文翻译：

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基于图像的“病原体箱”屏幕可识别具有抗贾第鞭毛虫活性的新化合物，并突出显示在表型药物发现中选择分析方法的重要性。

贾第鞭毛虫（Giardia duodenalis）是人类最普遍的肠道寄生虫病，引起贾第鞭毛虫病。每年十二指肠球菌感染约10亿人，其中约2.8亿患有症状性疾病。贾第鞭毛虫病可以是严重的和慢性的，导致儿童营养不良，生长发育迟缓和认知能力差。当前的治疗选择依赖于疗效和副作用下降的药物。为了改善全世界数百万人的健康和福祉，需要与目前使用的药物具有不同作用方式的新抗贾第鞭毛虫药物。疟疾药品风险投资公司的病原盒是一组专门选择来刺激传染病药物发现的生物活性化合物，为发现新的抗贾第鞭毛虫药物提供了机会。尽管已报道了病原体盒化合物的抗贾第鞭毛虫活性，但这项工作未能鉴定化合物集中已知的抗贾第鞭毛虫对照。它还报告了先前筛选并显示出对其他化合物无活性的化合物的活性，这表明数据可能不准确。考虑到这些问题，在当前研究中重新评估了病原盒化合物的抗贾第鞭毛虫活性。这项工作的数据确定了13种抗贾第鞭毛虫IC50值≤2μM的化合物。这些化合物中的五个是参考化合物（具有已知抗微生物活性的市售药物），或具有先前描述的抗贾第鞭毛虫活性的化合物的类似物。但是，包括MMV676358和MMV028694在内的八种药物显示出对组合A，B和甲硝唑耐药性寄生虫有效的亚μMIC50（分别为0.3μM和0.9μM），可能代表未来药物开发的新线索。有趣的是，在先前报道的“病原菌盒”屏幕中仅鉴定出了这些化合物中的四种，突显了评估化合物针对传染原的活性时分析选择和设计的重要性。