{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T11:59:33Z","timestamp":1781265573624,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,10]]},"group-title":"Genetics","reference-count":83,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["R01 AI154777"],"award-info":[{"award-number":["R01 AI154777"]}]},{"name":"Dr.Hilmer Stiftung grant","award":["T0146 \u2013 42.804"],"award-info":[{"award-number":["T0146 \u2013 42.804"]}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["P500PB_225631"],"award-info":[{"award-number":["P500PB_225631"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Cryptosporin, a fungal metabolite, exhibited potent antimalarial activity against both asexual blood stage\n                  <jats:italic>Plasmodium falciparum<\/jats:italic>\n                  and liver-stage\n                  <jats:italic>Plasmodium berghei<\/jats:italic>\n                  with minimal human HepG2 toxicity. Unlike atovaquone, cryptosporin\u2019s mechanism is independent of mitochondrial electron transport. Minimum inoculum of resistance showed a low risk of resistance development. RNA-Seq analysis revealed the upregulation of genes associated with sexual development including many canonical markers such as Pfs25, and PfCCp3, suggesting a stress response that is also seen when parasites are treated with artemisinin.\n                  <jats:italic>In vitro<\/jats:italic>\n                  evolution and whole genome sequencing analysis identified a mutation (F138Y) in PfAQP (PF3D7_1132800) and duplications of the two superoxide dismutase genes, PfSOD-1 (PF3D7_0814900) and PfSOD-2 (PF3D7_0623500). CRISPR\/Cas9 editing confirmed that the F138Y mutation in PfAQP was sufficient to confer resistance to cryptosporin. Alignment of the\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  structure with that of HsAQP3 suggests the mutation may impact transport of hydrogen peroxide and the transition between open and closed conformations. Indeed, studies with BY4742 \u0394fps1 yeast expressing PfAQP showed that the permeability of PfAQP was not affected by cryptosporin and that it is likely not a direct target. Taken together, this study highlights the role of PfAQP in the resistance development of cryptosporin. In addition, cryptosporin likely induces high levels of oxidative stress which results in the duplications of oxidative dismutase genes as part of the parasite\u2019s defense response. These findings highlight the role of PfAQP in mediating drug resistance, the mechanism of which warrants further research.\n                <\/jats:p>","DOI":"10.64898\/2026.06.08.730986","type":"posted-content","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T02:20:46Z","timestamp":1781144446000},"source":"Crossref","is-referenced-by-count":0,"title":["Duplication of superoxide dismutase and a mutation in aquaglyceroporin mediates the sensitivity of\n                  <i>Plasmodium falciparum<\/i>\n                  to cryptosporin, a natural product derived from\n                  <i>Acaromyces ingoldii<\/i>"],"prefix":"10.64898","author":[{"given":"Tiantian","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Collins","sequence":"additional","affiliation":[{"name":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Woo","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Duksung Women\u2019s University, Seoul, 01369, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Buss","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Kiel University, Gutenbergstr. 76, 24118 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basil T.","family":"Thommen","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca C.S.","family":"Edgar","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences, University of Dundee, Dundee, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Wendt","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, University of Michigan, 1007 East Huron Street, Ann Arbor, Michigan, 48104, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisy Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carissa","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimisha","family":"Mittal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphaella","family":"Paes","sequence":"additional","affiliation":[{"name":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia Mojica","family":"Santos","sequence":"additional","affiliation":[{"name":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia Tiburcio","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, 10032, United States"},{"name":"Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, 10032, United States"},{"name":"Laboratory of Tropical Diseases \u2013 Prof. Dr. Luiz Jacintho da Silva, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas-UNICAMP, Campinas, S\u00e3o Paulo, 13083-864, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasveen","family":"Bhasin","sequence":"additional","affiliation":[{"name":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremiah D.","family":"Momper","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Fidock","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, 10032, United States"},{"name":"Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, 10032, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Lee","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences, University of Dundee, Dundee, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj T.","family":"Duraisingh","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. 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