| Author | Fujii, Thais Tenorio Soares | |
| Author | Gomes, Pollyanna Stephanie | |
| Author | Monte Neto, Rubens Lima do | |
| Author | Gomes, Daniel Claudio de Oliveira | |
| Author | Ouellette, Marc | |
| Author | Santos, Eduardo Caio Torres | |
| Author | Andrade Neto, Valter Viana | |
| Author | Guedes, Herbert Leonel de Matos | |
| Access date | 2022-03-17T20:07:00Z | |
| Available date | 2022-03-17T20:07:00Z | |
| Document date | 2022 | |
| Citation | FUJII, Thais Tenorio et al. Simvastatin Resistance of Leishmania amazonensis Induces Sterol Remodeling and Cross-Resistance to Sterol Pathway and Serine Protease Inhibitors. Microorganisms, v. 10, 398, p. 1 - 20, Feb. 2022. | pt_BR |
| ISSN | 2076-2607 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/51732 | |
| Language | eng | pt_BR |
| Publisher | MDPI | pt_BR |
| Rights | open access | |
| Subject in Portuguese | Leishmania amazonensis | pt_BR |
| Subject in Portuguese | Via do esterol | pt_BR |
| Subject in Portuguese | HMG-CoA redutase | pt_BR |
| Subject in Portuguese | Resistência à sinvastatina | pt_BR |
| Subject in Portuguese | Alvo farmacológico | pt_BR |
| Subject in Portuguese | Proteases de serina | pt_BR |
| Title | Simvastatin Resistance of Leishmania amazonensis Induces Sterol Remodeling and Cross-Resistance to Sterol Pathway and Serine Protease Inhibitors | pt_BR |
| Type | Article | |
| DOI | 10.3390/ microorganisms10020398 | |
| Abstract | 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 sterolrelated
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- -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. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Biofisica Carlos Chagas Filho. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Laboratório de Imunobiotecnologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz-Fiocruz Minas. Instituto René Rachou. Grupo de Pesquisas em Biotecnologia Aplicada a Patógenos. Belo Horizonte, MG, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Espírito Santo. Núcleo de Doenças Infecciosas. Vitória, ES, Brasil. | pt_BR |
| Affilliation | 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. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Biofisica Carlos Chagas Filho. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Laboratório de Imunobiotecnologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Subject | Leishmania amazonensis | pt_BR |
| Subject | Sterol pathway | pt_BR |
| Subject | HMG-CoA reductase | pt_BR |
| Subject | Simvastatin resistance | pt_BR |
| Subject | Pharmacological target | pt_BR |
| Subject | Serine proteases | pt_BR |
