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Chemotherapy may fail either due to pre-existing resistance or evolution of drug-resistant parasites. Here we use a diverse set of antimalarial compounds to investigate the acquisition of drug resistance and the degree of cross-resistance against common resistance alleles. We assess cross-resistance using a set of 15 parasite lines carrying resistance-conferring alleles in <jats:italic>pfatp4<\/jats:italic>, cytochrome <jats:italic>bc<\/jats:italic><jats:sub><jats:italic>1<\/jats:italic><\/jats:sub>, <jats:italic>pfcarl<\/jats:italic>, <jats:italic>pfdhod, pfcrt<\/jats:italic>, <jats:italic>pfmdr, pfdhfr,<\/jats:italic> cytoplasmic prolyl t-RNA synthetase or <jats:italic>hsp90<\/jats:italic>. Subsequently, we assess whether resistant parasites can be obtained after several rounds of drug selection. Twenty-three of the 48 <jats:italic>in vitro<\/jats:italic> selections result in resistant parasites, with time to resistance onset ranging from 15 to 300 days. Our data indicate that pre-existing resistance may not be a major hurdle for novel-target antimalarial candidates, and focusing our attention on fast-killing compounds may result in a slower onset of clinical resistance.<\/jats:p>","DOI":"10.1038\/ncomms11901","type":"journal-article","created":{"date-parts":[[2016,6,15]],"date-time":"2016-06-15T17:14:38Z","timestamp":1466010878000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":122,"title":["A broad analysis of resistance development in the malaria parasite"],"prefix":"10.1038","volume":"7","author":[{"given":"Victoria C.","family":"Corey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda K.","family":"Lukens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva S.","family":"Istvan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus C. 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