Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani

Abstract

We evaluated the anti-leishmanial efficacy of different saturated medium-chain fatty acids (FAs, C8–C18) where FA containing C8 chain, caprylic acid (CA), was found to be most potent against Leishmania donovani, the causative agent for visceral leishmaniasis (VL). Different analogs of CA with C8 linear chain, but not higher, along with a carboxyl/ester group showed a similar anti-leishmanial effect. Ergosterol depletion was the major cause of CA-mediated cell death. Molecular docking and molecular dynamic simulation studies indicated the enzyme mevalonate kinase (MevK) of the ergosterol biosynthesis pathway as a possible target of CA. Enzyme assays with purified recombinant MevK and CA/CA analogs confirmed the target with a competitive inhibition pattern. Using biochemical and biophysical studies; strong binding interaction between MevK and CA/CA analogs was established. Further, using parasites with overexpressed MevK and proteomics studies of CA-treated parasites the direct role of MevK as the target was validated. We established the mechanism of the antileishmanial effect of CA, a natural product, against VL where toxicity and drug resistance with current chemotherapeutics demand an alternative. This is the first report on the identification of an enzymatic target with kinetic parameters and mechanistic insights against any organism for a natural medium-chain FA.

Propene-bridged cyanurate tetramers decorated on carbon nanosheets with antibacterial activity: insights from molecular modeling and in vitro studies

“…Enzymes that are part of the cell wall biosynthesis pathways have been identified as highly promising targets for discovering novel inhibitors. 27 To this end, we investigated…”

Characterization of novel mevalonate kinases from the tardigrade Ramazzottius varieornatus and the psychrophilic archaeon Methanococcoides burtonii

“…Many MKs have been characterized and studied, as they have been implicated in human diseases such as mevalonic aciduria, hyperimmunoglobulinemia D and periodic fever syndrome (Favier & Schulert, 2016). MKs are also potentially interesting drug targets, as they play essential roles in the metabolism of pathogenic organisms such as Leishmania (Shafi et al, 2021;Prasad et al, 2022) and in some eubacteria, for example Streptococcus pneumoniae (Kudoh et al, 2010) and Staphylococcus aureus (Ferrand et al, 2011).…”