{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:22:38Z","timestamp":1780633358668,"version":"3.54.1"},"reference-count":68,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T00:00:00Z","timestamp":1644364800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"National Council for Scientific and Technological Development","doi-asserted-by":"publisher","award":["310640\/2017-2"],"award-info":[{"award-number":["310640\/2017-2"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>The sterol biosynthesis pathway of Leishmania spp. is used as a pharmacological target; however, available information about the mechanisms of the regulation and remodeling of sterol-related genes is scarce. The present study investigated compensatory mechanisms of the sterol biosynthesis pathway using an inhibitor of HMG-CoA reductase (simvastatin) and by developing drug-resistant parasites to evaluate the impact on sterol remodeling, cross-resistance, and gene expression. Simvastatin-resistant L. amazonensis parasites (LaSimR) underwent reprogramming of sterol metabolism manifested as an increase in cholestane- and stigmastane-based sterols and a decrease in ergostane-based sterols. The levels of the transcripts of sterol 24-C-methyltransferase (SMT), sterol C14-\u03b1-demethylase (C14DM), and protease subtilisin (SUB) were increased in LaSimR. LaSimR was cross-resistance to ketoconazole (a C14DM inhibitor) and remained sensitive to terbinafine (an inhibitor of squalene monooxygenase). Sensitivity of the LaSimR mutant to other antileishmanial drugs unrelated to the sterol biosynthesis pathway, such as trivalent antimony and pentamidine, was similar to that of the wild-type strain; however, LaSimR was cross-resistant to miltefosine, general serine protease inhibitor N-p-tosyl-l-phenylalanine chloromethyl ketone (TPCK), subtilisin-specific inhibitor 4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-(3R)-3-pyrrolidinyl-benzamide dihydrochloride (PF-429242), and tunicamycin. The findings on the regulation of the sterol pathway can support the development of drugs and protease inhibitors targeting this route in parasites.<\/jats:p>","DOI":"10.3390\/microorganisms10020398","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T23:37:48Z","timestamp":1644363468000},"page":"398","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Simvastatin Resistance of Leishmania amazonensis Induces Sterol Remodeling and Cross-Resistance to Sterol Pathway and Serine Protease Inhibitors"],"prefix":"10.3390","volume":"10","author":[{"given":"Thais Tenorio Soares","family":"Fujii","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Instituto de Biof\u00edsica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pollyanna Stephanie","family":"Gomes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunobiotecnologia, Instituto de Microbiologia Paulo de G\u00f3es, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil"},{"name":"Laborat\u00f3rio Interdisciplinar de Pesquisas M\u00e9dicas, Instituto Oswaldo Cruz, Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4688-2462","authenticated-orcid":false,"given":"Rubens Lima","family":"do Monte-Neto","sequence":"additional","affiliation":[{"name":"Grupo de Pesquisas em Biotecnologia Aplicada a Pat\u00f3genos\u2014Instituto Ren\u00e9 Rachou, Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz Minas, Belo Horizonte 30190-002, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Claudio","family":"de Oliveira Gomes","sequence":"additional","affiliation":[{"name":"N\u00facleo de Doen\u00e7as Infecciosas, Universidade Federal do Esp\u00edrito Santo, Vit\u00f3ria 29075-910, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ouellette","sequence":"additional","affiliation":[{"name":"CHU de Quebec Research Center, Division of Infectious Disease and Immunity, Department of Microbiology Infectious Disease and Immunology, Laval University, Quebec, QC G1V 4G2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2240-4519","authenticated-orcid":false,"given":"Eduardo Caio","family":"Torres-Santos","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioqu\u00edmica de Tripanosomat\u00eddeos, Instituto Oswaldo Cruz, Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8854-1896","authenticated-orcid":false,"given":"Valter Viana","family":"Andrade-Neto","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioqu\u00edmica de Tripanosomat\u00eddeos, Instituto Oswaldo Cruz, Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert Leonel","family":"de Matos Guedes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Instituto de Biof\u00edsica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil"},{"name":"Laborat\u00f3rio de Imunobiotecnologia, Instituto de Microbiologia Paulo de G\u00f3es, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil"},{"name":"Laborat\u00f3rio Interdisciplinar de Pesquisas M\u00e9dicas, Instituto Oswaldo Cruz, Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,9]]},"reference":[{"key":"ref_1","first-page":"642502","article-title":"Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs","volume":"2009","author":"Rodrigues","year":"2009","journal-title":"Interdiscip. 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