{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T01:10:19Z","timestamp":1790298619544,"version":"4.1.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T00:00:00Z","timestamp":1564531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100012947","name":"the Institut de Recherche pour le D\u00e9veloppement","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012947","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004794","name":"Centre National de la Recherche Scientifique","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004794","id-type":"DOI","asserted-by":"crossref"}]},{"name":"French Ministry of Research"},{"name":"the Centre Hospitalier Universitaire"},{"name":"Laboratoire d\u2019Excellence"},{"name":"French Parasitology Alliance for Health Care","award":["ANR-11-LABX-0024"],"award-info":[{"award-number":["ANR-11-LABX-0024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>For almost a century, antimonials have remained the first-line drugs for the treatment of leishmaniasis. However, little is known about their mode of action and clinical resistance mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We have previously shown that Leishmania nicotinamidase (PNC1) is an essential enzyme for parasite NAD+ homeostasis and virulence in vivo. Here, we found that parasites lacking the pnc1 gene (\u0394pnc1) are hypersusceptible to the active form of antimony (SbIII) and used these mutant parasites to better understand antimony\u2019s mode of action and the mechanisms leading to resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>SbIII-resistant WT and \u0394pnc1 parasites were selected in vitro by a stepwise selection method. NAD(H)\/NADP(H) dosages and quantitative RT\u2013PCR experiments were performed to explain the susceptibility differences observed between strains. WGS and a marker-free CRISPR\/Cas9 base-editing approach were used to identify and validate the role of a new resistance mutation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NAD+-depleted \u0394pnc1 parasites were highly susceptible to SbIII and this phenotype could be rescued by NAD+ precursor or trypanothione precursor supplementation. \u0394pnc1 parasites could become resistant to SbIII by an unknown mechanism. WGS revealed a unique amino acid substitution (H451Y) in an EF-hand domain of an orphan calcium-dependent kinase, recently named SCAMK. When introduced into a WT reference strain by base editing, the H451Y mutation allowed Leishmania parasites to survive at extreme concentrations of SbIII, potentiating the rapid emergence of resistant parasites.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results establish that Leishmania SCAMK is a new central hub of antimony\u2019s mode of action and resistance development, and uncover the importance of drug tolerance mutations in the evolution of parasite drug resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkz334","type":"journal-article","created":{"date-parts":[[2019,7,10]],"date-time":"2019-07-10T15:09:34Z","timestamp":1562771374000},"page":"3231-3239","source":"Crossref","is-referenced-by-count":12,"title":["A single amino acid substitution (H451Y) in Leishmania calcium-dependent kinase SCAMK confers high tolerance and resistance to antimony"],"prefix":"10.1093","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9640-2009","authenticated-orcid":false,"given":"Baptiste","family":"Vergnes","sequence":"first","affiliation":[{"name":"MIVEGEC, IRD, CNRS, Univ. 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