AUTHOR=Groomes Patrice V. , Paul Aditya S. , Duraisingh Manoj T. 

TITLE=Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2024.1304839

DOI=10.3389/fcimb.2024.1304839

ISSN=2235-2988

ABSTRACT=<sec><title>Background</title><p>Chemotherapies for malaria and babesiosis frequently succumb to the emergence of pathogen-related drug-resistance. Host-targeted therapies are thought to be less susceptible to resistance but are seldom considered for treatment of these diseases.</p></sec><sec><title>Methods</title><p>Our overall objective was to systematically assess small molecules for host cell-targeting activity to restrict proliferation of intracellular parasites. We carried out a literature survey to identify small molecules annotated for host factors implicated in <italic>Plasmodium falciparum</italic> infection. Alongside <italic>P. falciparum</italic>, we implemented <italic>in vitro</italic> parasite susceptibility assays also in the zoonotic parasite <italic>Plasmodium knowlesi</italic> and the veterinary parasite <italic>Babesia divergens</italic>. We additionally carried out assays to test directly for action on RBCs apart from the parasites. To distinguish specific host-targeting antiparasitic activity from erythrotoxicity, we measured phosphatidylserine exposure and hemolysis stimulated by small molecules in uninfected RBCs.</p></sec><sec><title>Results</title><p>We identified diverse RBC target-annotated inhibitors with <italic>Plasmodium</italic>-specific, <italic>Babesia-</italic>specific, and broad-spectrum antiparasitic activity. The anticancer MEK-targeting drug trametinib is shown here to act with submicromolar activity to block proliferation of <italic>Plasmodium</italic> spp. in RBCs. Some inhibitors exhibit antimalarial activity with transient exposure to RBCs prior to infection with parasites, providing evidence for host-targeting activity distinct from direct inhibition of the parasite.</p></sec><sec><title>Conclusions</title><p>We report here characterization of small molecules for antiproliferative and host cell-targeting activity for malaria and babesiosis parasites. This resource is relevant for assessment of physiological RBC-parasite interactions and may inform drug development and repurposing efforts.</p></sec>