Paclitaxel-induced tubulin dysfunction stalls parasite development: synergistic potential with artemisinin against resistant strains

ABSTRACT In this study, paclitaxel (PTX), a well-characterized microtubule-stabilizing agent, was systematically investigated for its antimalarial potential against drug-resistant Plasmodium falciparum. In vitro experiments demonstrated that PTX potently inhibits intraerythrocytic development of drug-sensitive and -resistant strains, including chloroquine-resistant and artemisinin-resistant parasite lines, with 72-h half-maximal inhibitory concentrations (IC₅₀) ranging from 83.67 to 92.75 nM. PTX arrests parasite schizogony and reduces merozoite formation by ~25.69% to 37.46% when exposed to the trophozoite/schizont stage. Meanwhile, time-dependent drug activity against gametocyte maturation demonstrated that treatment during the immature gametocyte stages elicited a significant reduction in final gametocytemia (~38.24% to 58.79%), thereby validating the dual-targeting potential of PTX against both the pathogenic asexual and transmission-competent sexual parasite stages. Molecular dynamics simulations suggested that PTX was capable of binding to P. falciparum β-tubulin and potentially induced structural perturbations, including complex stabilization, enhanced M-loop flexibility, and global compaction, which may, in turn, disrupt microtubule dynamics. These results provide a plausible molecular basis for the antimalarial mechanism of PTX. Critically, PTX exhibits robust synergism with dihydroartemisinin (DHA) against artemisinin-resistant strains, reducing ring-stage survival to 1% and addressing the global challenge of artemisinin resistance. In vivo assays revealed that the PTX-DHA combination achieves near-complete parasite clearance (96% in humanized P. falciparum models. This finding confirms PTX’s translational potential and positions it as a novel tubulin-targeting partner for DHA, offering a promising strategy to combat drug-resistant malaria while safeguarding the efficacy of artemisinin-based combination therapies. IMPORTANCE In the current landscape of next-generation antimalarial development, preference will be given to compounds with activity against emerging drug-resistant parasite strains. However, identifying such effective molecules through traditional diversity library screenings remains challenging. As a result, the repurposing of old drugs has emerged as a prevalent and pragmatic strategy in the search for novel antimalarial agents. Our findings highlight a significant enhancement in combinatorial therapeutic efficacy, positioning paclitaxel as a promising partner drug for overcoming emerging drug resistance in malaria parasites. Therefore, we believe that this work will confer a broad interest to the readers of different disciplines, including antimalarial development.