{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T18:57:19Z","timestamp":1791485839671,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014682","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000}}],"reference-count":91,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"One Health Innovation Seed Grant"},{"name":"Texas Tech University Health Science Center Start-up","id":[{"id":"https:\/\/ror.org\/033ztpr93","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Persistence - characterized by the transient ability of subpopulations of\n                    <jats:italic>Leishmania<\/jats:italic>\n                    parasites to survive exposure to drugs - is a major driver of treatment failure and clinical relapses in leishmaniasis. Persisters are characterized by non-dividing or slow-growing state and increased drug tolerance. However, the molecular mechanisms governing formation of persisters remain poorly understood in\n                    <jats:italic>Leishmania<\/jats:italic>\n                    parasites. Here, we developed a model to explore persistence in\n                    <jats:italic>Leishmania mexicana<\/jats:italic>\n                    . Viable promastigote persister-like subpopulations were enriched using Ficoll density gradient centrifugation following lethal exposure to potassium antimonyl tartrate (PAT) that killed 80% of parasites. The surviving parasites exhibited delayed growth in drug-free medium that is characteristic for persisters, and higher drug tolerance upon rechallenge. Transcriptomic profiling across acute stress, drug-free recovery, and rechallenge phases revealed a global remodeling in persister-like cells under all tested conditions. Induction was characterized by downregulation of several biological processes and a robust upregulation of nucleolar pathways, supporting epitranscriptomic changes during the formation of persister-like cells. Upon drug removal, this profile rapidly reverted, initiating ribosome biogenesis to exit latency and resume proliferation. Resuscitation phase exhibited active protein synthesis and upregulation in biological processes associated with metabolic and mitochondrial functions. Furthermore, persister-like parasites displayed distinct drug response profiles compared to parental parasites by rapidly implementing a highly conserved, coordinated survival reprogramming, where 316 genes were uniquely downregulated, and 241 genes were upregulated. The distinct features of the drug response in rechallenged persister-like cells were characterized by the downregulation of mitochondrial function and protein synthesis to induce dormant state, and the upregulation of drug-response and stress-tolerance genes to survive immediate toxicity. In contrast, parental parasites displayed a broad and disorganized drug response. Additionally, rechallenged persisters exhibited distinct transcriptomic features that transiently phenocopies stable genetic resistance. This pre-adapted state is characterized by the targeted upregulation of epigenetic and epitranscriptomic modulators, heavy metal transporters, and catabolic enzymes to maintain viability. These findings demonstrate that drug persistence in\n                    <jats:italic>Leishmania<\/jats:italic>\n                    is not merely a metabolic collapse, but rather a sophisticated survival strategy involving active transcriptome remodeling, downregulation of translation and epigenetic\/epitranscriptomic changes. This transient state constitutes an initial evolutionary step toward permanent drug resistance and highlights new molecular vulnerabilities for therapeutic interventions aimed at preventing clinical relapse.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014682","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:44:50Z","timestamp":1791222290000},"page":"e1014682","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Active transcriptome remodeling underlies antimony-induced drug tolerance in persister-like Leishmania parasites"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5339-8978","authenticated-orcid":true,"given":"Eyson","family":"Quiceno","sequence":"first","affiliation":[{"name":"Texas Tech University Health Sciences Center","place":["Lubbock, Texas, United States of America"],"department":["Department of Cell Biology and Biochemistry"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9725-209X","authenticated-orcid":true,"given":"Cristian Camilo","family":"Rodr\u00edguez-Almonacid","sequence":"additional","affiliation":[{"name":"Texas Tech University Health Sciences Center","place":["Lubbock, Texas, United States of America"],"department":["Department of Cell Biology and Biochemistry"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4351-6570","authenticated-orcid":true,"given":"Khalid","family":"Omeir","sequence":"additional","affiliation":[{"name":"Texas Tech University","place":["Lubbock, Texas, United States of America"],"department":["Department of Biological Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1123-5841","authenticated-orcid":true,"given":"Jacob","family":"Ancira","sequence":"additional","affiliation":[{"name":"Texas Tech University","place":["Lubbock, Texas, United States of America"],"department":["Department of Biological Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9839-1510","authenticated-orcid":true,"given":"Caleb","family":"Phillips","sequence":"additional","affiliation":[{"name":"Texas Tech University","place":["Lubbock, Texas, United States of America"],"department":["Department of Biological Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1589-0216","authenticated-orcid":true,"given":"Zemfira N.","family":"Karamysheva","sequence":"additional","affiliation":[{"name":"Texas Tech University Health Sciences Center","place":["Lubbock, Texas, United States of America"],"department":["Department of Cell Biology and Biochemistry"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"issue":"2","key":"ppat.1014682.ref001","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1515\/jtim-2015-0002","article-title":"Leishmaniasis revisited: Current aspects on epidemiology, diagnosis and treatment","volume":"3","author":"SP Georgiadou","year":"2015","journal-title":"J Transl Int Med"},{"key":"ppat.1014682.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mam.2016.11.012","article-title":"Leishmania infections: Molecular targets and diagnosis","volume":"57","author":"M Akhoundi","year":"2017","journal-title":"Mol Aspects Med"},{"issue":"11","key":"ppat.1014682.ref003","doi-asserted-by":"crossref","first-page":"258","DOI":"10.3390\/tropicalmed9110258","article-title":"Leishmaniasis in humans and animals: A one health approach for surveillance, prevention and control in a changing world","volume":"9","author":"C Cosma","year":"2024","journal-title":"Trop Med Infect Dis"},{"issue":"9","key":"ppat.1014682.ref004","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1001\/jamadermatol.2018.2133","article-title":"Incidence of endemic human cutaneous Leishmaniasis in the United States","volume":"154","author":"BE McIlwee","year":"2018","journal-title":"JAMA Dermatol"},{"issue":"1","key":"ppat.1014682.ref005","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pntd.0005581","article-title":"The rise of neglected tropical diseases in the \u201cnew Texas\u201d","volume":"12","author":"PJ Hotez","year":"2018","journal-title":"PLoS Negl Trop Dis"},{"issue":"3","key":"ppat.1014682.ref006","doi-asserted-by":"crossref","DOI":"10.1128\/msphere.00814-23","article-title":"Cutaneous Leishmania mexicana infections in the United States: Defining strains through endemic human pediatric cases in northern Texas","volume":"9","author":"B Nepal","year":"2024","journal-title":"mSphere"},{"issue":"3","key":"ppat.1014682.ref007","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1093\/femsre\/fux001","article-title":"Formation, physiology, ecology, evolution and clinical importance of bacterial persisters","volume":"41","author":"B Van den Bergh","year":"2017","journal-title":"FEMS Microbiol Rev"},{"issue":"7","key":"ppat.1014682.ref008","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.tim.2014.03.008","article-title":"Bacterial persisters: Formation, eradication, and experimental systems","volume":"22","author":"S Helaine","year":"2014","journal-title":"Trends Microbiol"},{"issue":"10","key":"ppat.1014682.ref009","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1007301","article-title":"Fungal persister cells: The basis for recalcitrant infections?","volume":"14","author":"J Wuyts","year":"2018","journal-title":"PLoS 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persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins","volume":"188","author":"N V\u00e1zquez-Laslop","year":"2006","journal-title":"J Bacteriol"},{"issue":"3","key":"ppat.1014682.ref029","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1128\/AAC.02135-12","article-title":"Arrested protein synthesis increases persister-like cell formation","volume":"57","author":"BW Kwan","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"issue":"8042","key":"ppat.1014682.ref030","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/s41586-024-08124-2","article-title":"Identification and genetic dissection of convergent persister cell states","volume":"636","author":"SB Blattman","year":"2024","journal-title":"Nature"},{"key":"ppat.1014682.ref031","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.semcancer.2020.12.022","article-title":"Targeting epigenetic regulatory machinery to overcome cancer therapy 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quiescence\/senescence and drug resilience","volume":"15","author":"J Tripathi","year":"2024","journal-title":"Nat Commun"},{"key":"ppat.1014682.ref035","article-title":"Spontaneous dormancy protects Trypanosoma cruzi during extended drug exposure","volume":"7","author":"FJ S\u00e1nchez-Vald\u00e9z","year":"2018","journal-title":"Elife"},{"issue":"11","key":"ppat.1014682.ref036","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1011627","article-title":"Benznidazole treatment leads to DNA damage in Trypanosoma cruzi and the persistence of rare widely dispersed non-replicative amastigotes in mice","volume":"19","author":"S Jayawardhana","year":"2023","journal-title":"PLoS Pathog"},{"issue":"9","key":"ppat.1014682.ref037","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.3390\/microorganisms11092248","article-title":"Molecular mechanisms of persistence in protozoan parasites","volume":"11","author":"A Tarannum","year":"2023","journal-title":"Microorganisms"},{"issue":"5","key":"ppat.1014682.ref038","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1619265114","article-title":"Continual renewal and replication of persistent Leishmania major parasites in concomitantly immune hosts","volume":"114","author":"MA Mandell","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"ppat.1014682.ref039","doi-asserted-by":"crossref","first-page":"835","DOI":"10.3390\/pathogens13100835","article-title":"Molecular mechanisms of drug resistance in Leishmania spp","volume":"13","author":"MJ Moncada-Diaz","year":"2024","journal-title":"Pathogens"},{"key":"ppat.1014682.ref040","doi-asserted-by":"crossref","first-page":"1573618","DOI":"10.3389\/fmolb.2025.1573618","article-title":"Unravelling drug resistance in leishmaniasis: Genomic adaptations and emerging therapies","volume":"12","author":"CK Bhusal","year":"2025","journal-title":"Front Mol 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