Author:
Prasad Surendra Rajit,Kumar Prakash,Mandal Saptarshi,Mohan Anu,Chaurasia Radhika,Shrivastava Ashish,Nikhil Pallaprolu,Aishwarya Dande,Ramalingam P.,Gajbhiye Rahul,Singh Shriya,Dasgupta Arunava,Chourasia Mukesh,Ravichandiran V.,Das Prolay,Mandal Debabrata
Abstract
AbstractWe 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.
Funder
Department of Chemicals and Petrochemicals, Ministry of Chemicals and Fertilizers, India
Ministry of Education, India
Council of Scientific and Industrial Research, India
Publisher
Springer Science and Business Media LLC
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