Article
Simvastatin Resistance of Leishmania amazonensis Induces Sterol Remodeling and Cross-Resistance to Sterol Pathway and Serine Protease Inhibitors
Registro en:
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.
2076-2607
10.3390/ microorganisms10020398
Autor
Fujii, Thais Tenorio Soares
Gomes, Pollyanna Stephanie
Monte Neto, Rubens Lima do
Gomes, Daniel Claudio de Oliveira
Ouellette, Marc
Santos, Eduardo Caio Torres
Andrade Neto, Valter Viana
Guedes, Herbert Leonel de Matos
Resumen
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.