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Whole-genome sequencing of 18 parasite clones evolved using thienopyrimidine compounds with submicromolar, rapid-killing, pan\u2013life cycle antiparasitic activity showed that all had acquired mutations in the\n            <jats:italic>P. falciparum<\/jats:italic>\n            cytoplasmic isoleucyl tRNA synthetase (cIRS). Engineering two of the mutations into drug-na\u00efve parasites recapitulated the resistance phenotype, and parasites with conditional knockdowns of cIRS became hypersensitive to two thienopyrimidines. Purified recombinant\n            <jats:italic>P. vivax<\/jats:italic>\n            cIRS inhibition, cross-resistance, and biochemical assays indicated a noncompetitive, allosteric binding site that is distinct from that of known cIRS inhibitors mupirocin and reveromycin A.\u00a0Our data show that\n            <jats:italic>Plasmodium<\/jats:italic>\n            cIRS is an important chemically and genetically validated target for next-generation medicines for malaria.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adc9249","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T18:58:08Z","timestamp":1678301888000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":29,"title":["Cytoplasmic isoleucyl tRNA synthetase as an attractive multistage antimalarial drug 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