Journal
MICROORGANISMS
Volume 10, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/microorganisms10020398
Keywords
Leishmania amazonensis; sterol pathway; HMG-CoA reductase; simvastatin resistance; pharmacological target; serine proteases
Categories
Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico do Brasil (CNPq)
- FundacAo de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
- CAPES
- CIHR Foundation grant
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The study investigates the compensatory mechanisms of the sterol biosynthesis pathway in Leishmania parasites, revealing the important role of programmed regulation and gene expression in drug resistance. These findings have implications for the development of drugs and protease inhibitors targeting parasites.
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-alpha -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.
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