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Researchers investigated pentachloropseudilin (PCIP), a myosin inhibitor, against the parasite Toxoplasma gondii and found it disrupts multiple stages of the parasite's life cycle by targeting several different myosin proteins simultaneously. Using advanced imaging techniques, they identified that PCIP blocks parasite movement and invasion, prevents proper cell division by interfering with internal structure assembly, and causes defects in mature parasite cells that prevent them from exiting host cells. The study associates these distinct effects with disruption of three specific myosin proteins: MyoA, MyoF, and MyoJ.
Why it matters
This research validates a multi-target drug strategy against apicomplexan parasites like Toxoplasma, which cause significant disease in humans and animals. By demonstrating that a single compound can simultaneously disrupt multiple essential parasite functions, the findings suggest a promising approach for developing more effective antiparasitic drugs with potentially reduced resistance development.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
The pharmacological targeting of apicomplexan myosins has emerged as a validated antiparasitic strategy, with selective inhibitors of MyoA demonstrating activity against parasite motility and invasion. However, apicomplexan parasites express multiple unconventional myosins with essential functions throughout their life cycles that remain unexplored pharmacologically. Here, we investigated pentachloropseudilin (PCIP), a reversible allosteric inhibitor characterized against class-I myosins, although canonical class-I myosins are absent from Apicomplexa. Structural modeling predicted PCIP- potentially compatible allosteric pockets in several parasite myosins, including MyoA, MyoF and MyoJ, suggesting interference with multiple myosin-dependent processes. To specifically resolve PCIP-induced phenotypes across the tachyzoite lytic cycle, we combined complementary high-content and high-resolution approaches, including real-time live-cell imaging, quantitative assays and ultrastructure expansion microscopy. This identified distinct steps at which parasite progression was impaired. PCIP rapidly and reversibly inhibited gliding motility and host-cell invasion in a dose- dependent manner within the submicromolar range. A pronounced effect was observed during intracellular development, where PCIP inhibited proliferation and arrested parasites near the onset of daughter-cell budding. Live imaging and expansion microscopy revealed failure to assemble daughter inner membrane complex scaffolds and subpellicular microtubule arrays, and to replicate apicoplast, consistent with disruption of MyoF-dependent processes. This arrest was not simply cytostatic, as even short PCIP exposure prevented a substantial proportion of intracellular tachyzoites from resuming replication following drug removal. At lower concentrations permitting daughter-cell formation, progeny displayed defective final maturation and frequently lost plasma-membrane integrity within an intact parasitophorous vacuole, preventing egress consistent with interference with MyoJ-dependent processes. Together, these findings reveal multiple points of PCIP-induced failure throughout the T. gondii lytic cycle and associate distinct phenotypes with MyoA-, MyoF- and MyoJ-dependent functions. They establish PCIP as a chemical probe for dissecting apicomplexan myosin-dependent processes and support multi-myosin interference as a promising antiparasitic strategy.