Mode of action of fenarimol against Leishmania spp.
This paper evaluates the effects of certain herbicides on Leishmania spp., their mechanism of action, and the evolutionary origin of the relevant susceptible leishmanial targets. We demonstrated that a relatively nontoxic herbicide, fenarimol, successfully interferes with a leishmanial target, which is probably a relic of an ancient ancestor. Fenarimol impairs the function of leishmanial 14alpha-sterol demethylase, a key enzyme in the sterol biosynthetic pathway. Therefore, fenarimol or its derivatives may be candidates for development of anti-leishmanial drugs. Of the herbicides that have the capability to act as potential inhibitors of the metabolism of Leishmania spp., fenarimol was found as the most active substance against both promastigotes and amastigotes in culture. In addition, it ameliorated lesions caused by Leishmania major in mice. Light microscopy demonstrated rounding of the parasite shape. Increase of osmophilic vacuoles and autophagosomal structures were observed by transmission electron microscopy. Biochemical studies demonstrated that fenarimol inhibited sterol biosynthesis. Docking of fenarimol to the modeled catalytic binding site of 14alpha-lanosterol demethylase of L. major showed a geometrical fit. Fenarimol is stabilized via hydrophobic interactions with the residues that surround it and interactions with the heme ring. These results provide support to the hypothesis that fenarimol inhibits leishmanial sterol biosynthesis. Overall, the findings suggest an additional source of substances for development of anti-leishmanial drugs.
Zeiman
Einat
E
Department of Parasitology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel 91120.
Greenblatt
Charles L
CL
Elgavish
Sharona
S
Khozin-Goldberg
Ina
I
Golenser
Jacob
J
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000187:drug effects; D005260:Female; D006367:HeLa Cells / Q000187:drug effects; D006540:Herbicides / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007891:Leishmania / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007893:Leishmania donovani / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018320:Leishmania major / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D008958:Models, Molecular; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D013047:Specific Pathogen-Free Organisms; D058886:Sterol 14-Demethylase
D000981:Antiprotozoal Agents; C548418:CYP51A1 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D006540:Herbicides; D008024:Ligands; D011743:Pyrimidines; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase; C033789:fenarimol