Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/145209
Title: Whole-cell phenotypic screening of Medicines for Malaria Venture Pathogen Box identifies specific inhibitors of Plasmodium falciparum late-stage development and egress
Authors: Patra, Alok Tanala
Hingamire, Tejashri
Belekar, Meenakshi A.
Xiong, Aoli
Subramanian, Gowtham
Bozdech, Zbynek
Preiser, Peter
Shanmugam, Dhanasekaran
Chandramohanadas, Rajesh
Keywords: Science::Biological sciences
Issue Date: 2020
Source: Patra, 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.01802-19
Journal: Antimicrobial Agents and Chemotherapy
Abstract: We 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.
URI: https://hdl.handle.net/10356/145209
ISSN: 0066-4804
DOI: 10.1128/AAC.01802-19
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.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

SCOPUSTM   
Citations 50

4
Updated on Dec 3, 2022

Web of ScienceTM
Citations 50

4
Updated on Dec 6, 2022

Page view(s)

137
Updated on Dec 9, 2022

Download(s) 50

88
Updated on Dec 9, 2022

Google ScholarTM

Check

Altmetric


Plumx

Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.