Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/145209
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dc.contributor.authorPatra, Alok Tanalaen_US
dc.contributor.authorHingamire, Tejashrien_US
dc.contributor.authorBelekar, Meenakshi A.en_US
dc.contributor.authorXiong, Aolien_US
dc.contributor.authorSubramanian, Gowthamen_US
dc.contributor.authorBozdech, Zbyneken_US
dc.contributor.authorPreiser, Peteren_US
dc.contributor.authorShanmugam, Dhanasekaranen_US
dc.contributor.authorChandramohanadas, Rajeshen_US
dc.date.accessioned2020-12-15T04:43:12Z-
dc.date.available2020-12-15T04:43:12Z-
dc.date.issued2020-
dc.identifier.citationPatra, A. T., Hingamire, T., Belekar, M. A., Xiong, A., Subramanian, G., Bozdech, Z., . . . Chandramohanadas, R. (2020). Whole-cell phenotypic screening of Medicines for Malaria Venture Pathogen Box identifies specific inhibitors of Plasmodium falciparum late-stage development and egress. Antimicrobial Agents and Chemotherapy, 64(5), e01802-19-. doi:10.1128/AAC.01802-19en_US
dc.identifier.issn0066-4804en_US
dc.identifier.urihttps://hdl.handle.net/10356/145209-
dc.description.abstractWe report a systematic, cellular phenotype-based antimalarial screening of the Medicines for Malaria Venture Pathogen Box collection, which facilitated the identification of specific blockers of late-stage intraerythrocytic development of Plasmodium falciparum First, from standard growth inhibition assays, we identified 173 molecules with antimalarial activity (50% effective concentration [EC50] ≤ 10 μM), which included 62 additional molecules over previously known antimalarial candidates from the Pathogen Box. We identified 90 molecules with EC50 of ≤1 μM, which had significant effect on the ring-trophozoite transition, while 9 molecules inhibited the trophozoite-schizont transition and 21 molecules inhibited the schizont-ring transition (with ≥50% parasites failing to proceed to the next stage) at 1 μM. We therefore rescreened all 173 molecules and validated hits in microscopy to prioritize 12 hits as selective blockers of the schizont-ring transition. Seven of these molecules inhibited the calcium ionophore-induced egress of Toxoplasma gondii, a related apicomplexan parasite, suggesting that the inhibitors may be acting via a conserved mechanism which could be further exploited for target identification studies. We demonstrate that two molecules, MMV020670 and MMV026356, identified as schizont inhibitors in our screens, induce the fragmentation of DNA in merozoites, thereby impairing their ability to egress and invade. Further mechanistic studies would facilitate the therapeutic exploitation of these molecules as broadly active inhibitors targeting late-stage development and egress of apicomplexan parasites relevant to human health.en_US
dc.description.sponsorshipMinistry of Education (MOE)en_US
dc.language.isoenen_US
dc.relation.ispartofAntimicrobial Agents and Chemotherapyen_US
dc.rights© 2020 American Society for Microbiology. All rights reserved. This paper was published in Antimicrobial Agents and Chemotherapy and is made available with permission of American Society for Microbiology.en_US
dc.subjectScience::Biological sciencesen_US
dc.titleWhole-cell phenotypic screening of Medicines for Malaria Venture Pathogen Box identifies specific inhibitors of Plasmodium falciparum late-stage development and egressen_US
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.identifier.doi10.1128/AAC.01802-19-
dc.description.versionPublished versionen_US
dc.identifier.pmid32071059-
dc.identifier.issue5en_US
dc.identifier.volume64en_US
dc.subject.keywordsPhenotypic Screeningen_US
dc.subject.keywordsPlasmodium Falciparumen_US
dc.description.acknowledgementA.T.P., G.S., and R.C. acknowledge the following grants: RGAST1503 (A*star-India Collaboration grant) and T1MOE1702 (a Ministry of Education [MoE] Tier 1grant awarded through SUTD). A.T.P. acknowledges the MoE, Singapore, for a president’s graduate fellowship. The infrastructure support provided through the SUTD-MIT International Design Centre (IDC) is greatly acknowledged. M.A.B. and T.H. acknowledge Ph.D. fellowships from the Council of Scientific and Industrial Research, India; D.S.acknowledges the Indo-Singapore Joint Science and Technology Research Cooperationgrant from the Department of Science and Technology, India (grant INT/SIN/P-09/2015), and infrastructure support from the CSIR-National Chemical Laboratory, Pune, India.en_US
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