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 14α-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 14α-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.
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February 2008
Research Article|
February 01 2008
Mode of Action of Fenarimol Against Leishmania Spp.
Einat Zeiman;
Einat Zeiman
Department of Parasitology, The Hebrew University–Hadassah Medical School, Jerusalem, Israel 91120. golenser@md.huji.ac.il
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Charles L. Greenblatt;
Charles L. Greenblatt
Department of Parasitology, The Hebrew University–Hadassah Medical School, Jerusalem, Israel 91120. golenser@md.huji.ac.il
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Sharona Elgavish;
Sharona Elgavish
Department of Parasitology, The Hebrew University–Hadassah Medical School, Jerusalem, Israel 91120. golenser@md.huji.ac.il
* Department of Structural Biology Bioinformatics Unit, The Hebrew University–Hadassah Medical School, Jerusalem, Israel 91120
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Ina Khozin-Goldberg;
Ina Khozin-Goldberg
Department of Parasitology, The Hebrew University–Hadassah Medical School, Jerusalem, Israel 91120. golenser@md.huji.ac.il
† Blaustein Institute for Desert Research, Ben Gurion University of the Negev, Negev, Israel
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Jacob Golenser
Jacob Golenser
Department of Parasitology, The Hebrew University–Hadassah Medical School, Jerusalem, Israel 91120. golenser@md.huji.ac.il
‡ To whom correspondence should be addressed
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J Parasitol (2008) 94 (1): 280–286.
Citation
Einat Zeiman, Charles L. Greenblatt, Sharona Elgavish, Ina Khozin-Goldberg, Jacob Golenser; Mode of Action of Fenarimol Against Leishmania Spp.. J Parasitol 1 February 2008; 94 (1): 280–286. doi: https://doi.org/10.1645/GE-1259.1
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