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Lead antimalarial candidates are evaluated against clinical isolates to address key concerns regarding efficacy and to confirm that the current, circulating parasites from endemic regions lack resistance against these candidates. While this has largely been performed on ABS parasites, limited data are available on the transmission-blocking efficacy of compounds with multistage activity. Here, we evaluated the efficacy of lead antimalarial candidates against both ABS parasites and late-stage gametocytes side-by-side, against clinical\n              <jats:italic>P. falciparum<\/jats:italic>\n              isolates from southern Africa. We additionally correlated drug efficacy to the genetic diversity of the clinical isolates as determined with a panel of well-characterized, genome-spanning microsatellite markers. Our data indicate varying sensitivities of the isolates to key antimalarial candidates, both for ABS parasites and gametocyte stages. While ABS parasites were efficiently killed, irrespective of genetic complexity, antimalarial candidates lost some gametocytocidal efficacy when the gametocytes originated from genetically complex, multiple-clone infections. This suggests a fitness benefit to multiclone isolates to sustain transmission and reduce drug susceptibility. In conclusion, this is the first study to investigate the efficacy of antimalarial candidates on both ABS parasites and gametocytes from\n              <jats:italic>P. falciparum<\/jats:italic>\n              clinical isolates where the influence of parasite genetic complexity is highlighted, ultimately aiding the malaria elimination agenda.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01291-23","type":"journal-article","created":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T14:00:25Z","timestamp":1706018425000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Genetic complexity alters drug susceptibility of asexual and gametocyte stages of\n            <i>Plasmodium falciparum<\/i>\n            to antimalarial candidates"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3579-7251","authenticated-orcid":false,"given":"Nicola","family":"Greyling","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Pretoria, South Africa"},{"name":"Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u00ebtte","family":"van der Watt","sequence":"additional","affiliation":[{"name":"Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazel","family":"Gwarinda","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Pretoria, South Africa"},{"name":"Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashleigh","family":"van Heerden","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Pretoria, South Africa"},{"name":"Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0287-9111","authenticated-orcid":true,"given":"Bryan","family":"Greenhouse","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California-San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Leroy","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jandeli","family":"Niemand","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Pretoria, South Africa"},{"name":"Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5888-2905","authenticated-orcid":true,"given":"Lyn-Mari\u00e9","family":"Birkholtz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Pretoria, South Africa"},{"name":"Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","unstructured":"World Health Organization. 2022. 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