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Influence of simvastatin on the mevalonate pathway and the production of bacterial cell wall precursors: an antimicrobial mechanism of action

Abstract

Simvastatin is a cholesterol-lowering drug that has already demonstrated in vitro antimicrobial action against some species of microorganisms, including Staphylococcus aureus. Its mechanism of action as a lipid-lowering agent occurs by inhibiting the enzyme HMGCoA-reductase I in the pathway of mevalonate production in eukaryotic cells, whereas its mechanism of antimicrobial action is still unknown. Therefore, the objective of the present study is to evaluate the mechanism of action of simvastatin as an antimicrobial by evaluating the inhibition of the bacterial HMGCoA-reductase II enzyme and the production of S. aureus cell wall proteins. For the study of the bacterial mechanism of action of simvastatin, the bacterial enzyme HMG-CoA reductase II in S. aureus (Gram-positive bacteria that has the production of isoprenoids via the mevalonate) will be carried out, and in Escherichia coli (Gram negative bacteria producing isoprenoids via 2C-methyl-D-erythritol 4-phosphate (MEP)). Pravastatin, which has no antimicrobial activity against S. aureus, will be used as a standard of comparison for enzymatic inhibition. For this, assays of the enzymatic activity of HMGCo-A reductase II, mevalonate action on the antimicrobial effect of simvastatin, proteomic analysis of the cell wall proteins and quantification of the expression of the genes of the mevalonate pathway and wall peptidoglycan precursors cell by qRT-PCR will be performed. Further, transmission electron microscopies will be made to verify the integrity of the bacterial wall and cell membrane, structures that have isoprenoids in their composition. Thus, we expect, as results of the present study, that simvastatin inhibits the enzymatic activity of bacterial HMGCo-A reductase II, more pronounced than pravastatin, and in bacteria that have the mevalonate pathway, which would indicate that simvastatin promotes its antimicrobial action in this way. In addition, we expect to have morphological changes in the cell wall of S. aureus. Furthermore, we expect to find alterations in the production of surface proteins and the expression of genes related to the mevalonate pathway, which would contribute to elucidate the pathways of action of simvastatin. (AU)