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Patients with a depressed immune system, like the ones receiving methotrexate (MTX), are at higher risk of developing VL and refusing antileishmanial drugs. Moreover, the alarmingly growing levels of antimicrobial resistance, especially in endemic areas, contribute to the increasing the burden of this complex zoonotic disease.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Principal findings<\/jats:title>\n<jats:p>To understand the potential links between immunosuppressants and antileishmanial drugs, we have studied the interaction of antimony (Sb) and MTX in a <jats:italic>Leishmania infantum<\/jats:italic> reference strain (<jats:italic>Li<\/jats:italic>WT) and in two <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> clinical strains (<jats:italic>Li<\/jats:italic>FS-A and <jats:italic>Li<\/jats:italic>FS-B) naturally circulating in non-treated VL dogs in Spain. The <jats:italic>Li<\/jats:italic>FS-A strain was isolated before Sb treatment in a case that responded positively to the treatment, while the <jats:italic>Li<\/jats:italic>FS-B strain was recovered from a dog before Sb treatment, with the dog later relapsing after the treatment. Our results show that, exposure to Sb or MTX leads to an increase in the production of reactive oxygen species (ROS) in <jats:italic>Li<\/jats:italic>WT which correlates with a sensitive phenotype against both drugs in promastigotes and intracellular amastigotes. <jats:italic>Li<\/jats:italic>FS-A was sensitive against Sb but resistant against MTX, displaying high levels of protection against ROS when exposed to MTX. <jats:italic>Li<\/jats:italic>FS-B was resistant to both drugs. Evaluation of the melting proteomes of the two <jats:italic>Li<\/jats:italic>FS, in the presence and absence of Sb and MTX, showed a differential enrichment of direct and indirect targets for both drugs, including common and unique pathways.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Our results show the potential selection of Sb-MTX cross-resistant parasites in the field, pointing to the possibility to undermine antileishmanial treatment of those patients being treated with immunosuppressant drugs in <jats:italic>Leishmania<\/jats:italic> endemic areas.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0012015","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T18:56:45Z","timestamp":1709233005000},"page":"e0012015","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Potential selection of antimony and methotrexate cross-resistance in Leishmania infantum circulating strains"],"prefix":"10.1371","volume":"18","author":[{"given":"Lorena","family":"Bernardo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Victoria","family":"Ibarra-Meneses","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelie","family":"Douanne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Corbeil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Carlos","family":"Solana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Beaudry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Carrillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4834-4956","authenticated-orcid":true,"given":"Christopher","family":"Fernandez-Prada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,2,29]]},"reference":[{"key":"pntd.0012015.ref001","volume-title":"Manual on case management and surveillance of the leishmaniases in the WHO European Region","author":"L Gradoni","year":"2017"},{"key":"pntd.0012015.ref002","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/1297-9716-42-39","article-title":"Mechanisms of resistance and susceptibility to experimental visceral leishmaniosis: BALB\/c mouse versus Syrian hamster model","volume":"42","author":"A Nieto","year":"2011","journal-title":"Veterinary research"},{"key":"pntd.0012015.ref003","doi-asserted-by":"crossref","first-page":"e35671","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis worldwide and global estimates of its incidence","volume":"7","author":"J Alvar","year":"2012","journal-title":"PloS one"},{"key":"pntd.0012015.ref004","unstructured":"WHO. 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