An image-based Pathogen Box screen identifies new compounds with anti-Giardia activity and highlights the importance of assay choice in phenotypic drug discovery

• DOI: 10.1016/j.ijpddr.2020.03.002
• Publication Date: 2020-03-13T10:16:32Z
• Authors: Snigdha Tiash; Jake Saunders; Christopher J.S. ...; John H. Ryan; Andrew G. Riches; Tina S. Skinner-A...
• Keywords: Giardia; Giardia lamblia; Phenotypic screening; Human pathogen

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