NDLI: Antileishmanial effect of mevastatin is due to interference with sterol metabolism

Content Provider	Springer Nature Link
Author	Dinesh, Neeradi Soumya, Neelagiri Singh, Sushma
Copyright Year	2015
Abstract	Visceral leishmaniasis (VL) is one of the most severe forms of leishmaniasis which is fatal if left untreated. Sterol biosynthetic pathway in Leishmania is currently being explored for its therapeutic potential. In the present study, we have evaluated the antileishmanial efficacy of mevastatin, a known inhibitor of 3-hydroxy-3-methyl glutaryl-CoA reductase (HMGR) enzyme. Mevastatin inhibited Leishmania donovani promastigotes and intracellular amastigotes with an 50 % inhibitory concentration (IC50) value of 23.8 ± 4.2 and 7.5 ± 1.1 μM, respectively, without exhibiting toxicity towards host cell line. Mevastatin also inhibited recombinant L. donovani HMGR (LdHMGR) enzyme activity with an IC50 value of 42.2 ± 3.0 μM. Kinetic analysis revealed that the inhibition of recombinant LdHMGR activity by mevastatin was competitive with HMG-CoA. Mevastatin-treated parasites exhibited 66 % reduction in ergosterol levels with respect to untreated parasites. Incubation of mevastatin-treated L. donovani promastigotes with ergosterol resulted in revival of cell growth, whereas cholesterol supplementation failed to cause reversal in cell death. To further prove the specificity of mevastatin for HMGR enzyme, HMGR-overexpressing parasites were used which showed almost threefold resistance to mevastatin. It also induced morphological changes in the parasite accompanied by lipid body accumulation. Hence, antileishmanial effect of mevastatin was due to the inhibition of HMGR, which eventually leads to reduction in ergosterol levels and hence parasite death. The present study may have implications in the treatment of visceral form of leishmaniasis.
Starting Page	3873
Ending Page	3883
Page Count	11
File Format	PDF
ISSN	09320113
Journal	Parasitology Research
Volume Number	114
Issue Number	10
e-ISSN	14321955
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2015-07-18
Publisher Place	Berlin/Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Antileishmanial effect Mevastatin Sterol metabolism Medical Microbiology Microbiology Immunology
Content Type	Text
Resource Type	Article
Subject	Infectious Diseases Veterinary Parasitology Insect Science

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