This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chen, M.
Right arrow Articles by Kharazmi, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, M.
Right arrow Articles by Kharazmi, A.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 2001, p. 2023-2029, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2023-2029.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Inhibition of Fumarate Reductase in Leishmania major and L. donovani by Chalcones

Ming Chen,1,2,* Lin Zhai,1 Søren Brøgger Christensen,3 Thor G. Theander,4 and Arsalan Kharazmi1

Centre for Medical Parasitology, Department of Clinical Microbiology, University Hospital of Copenhagen,1 Statens Seruminstitut,2 Department of Medicinal Chemistry, The Royal Danish School of Pharmacy,3 and Institute for Medical Microbiology and Immunology, University of Copenhagen,4 Copenhagen, Denmark

Received 6 February 2001/Returned for modification 5 March 2001/Accepted 17 April 2001

Our previous studies have shown that chalcones exhibit potent antileishmanial and antimalarial activities in vitro and in vivo. Preliminary studies showed that these compounds destroyed the ultrastructure of Leishmania parasite mitochondria and inhibited the respiration and the activity of mitochondrial dehydrogenases of Leishmania parasites. The present study was designed to further investigate the mechanism of action of chalcones, focusing on the parasite respiratory chain. The data show that licochalcone A inhibited the activity of fumarate reductase (FRD) in the permeabilized Leishmania major promastigote and in the parasite mitochondria, and it also inhibited solubilized FRD and a purified FRD from L. donovani. Two other chalcones, 2,4-dimethoxy-4'-allyloxychalcone (24m4ac) and 2,4-dimethoxy-4'-butoxychalcone (24mbc), also exhibited inhibitory effects on the activity of solubilized FRD in L. major promastigotes. Although licochalcone A inhibited the activities of succinate dehydrogenase (SDH), NADH dehydrogenase (NDH), and succinate- and NADH-cytochrome c reductases in the parasite mitochondria, the 50% inhibitory concentrations (IC50) of licochalcone A for these enzymes were at least 20 times higher than that for FRD. The IC50 of licochalcone A for SDH and NDH in human peripheral blood mononuclear cells were at least 70 times higher than that for FRD. These findings indicate that FRD, one of the enzymes of the parasite respiratory chain, might be the specific target for the chalcones tested. Since FRD exists in the Leishmania parasite and does not exist in mammalian cells, it could be an excellent target for antiprotozoal drugs.

* Corresponding author. Mailing address: Department of Clinical Microbiology, 7806, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen N, Denmark. Phone: (45) 35 45 77 38. Fax: (45) 35 45 68 31. E-mail: cmcmp{at}rh.dk.

Antimicrobial Agents and Chemotherapy, July 2001, p. 2023-2029, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2023-2029.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Torres-Santos, E. C., Sampaio-Santos, M. I., Buckner, F. S., Yokoyama, K., Gelb, M., Urbina, J. A., Rossi-Bergmann, B. (2009). Altered sterol profile induced in Leishmania amazonensis by a natural dihydroxymethoxylated chalcone. J Antimicrob Chemother 63: 469-472 [Abstract] [Full Text]  
  • Li, A. H., Lam, W. L., Stokes, R. W. (2008). Characterization of genes differentially expressed within macrophages by virulent and attenuated Mycobacterium tuberculosis identifies candidate genes involved in intracellular growth. Microbiology 154: 2291-2303 [Abstract] [Full Text]  
  • Luque-Ortega, J. R., Rivas, L. (2007). Miltefosine (Hexadecylphosphocholine) Inhibits Cytochrome c Oxidase in Leishmania donovani Promastigotes. Antimicrob. Agents Chemother. 51: 1327-1332 [Abstract] [Full Text]  
  • Coustou, V., Besteiro, S., Riviere, L., Biran, M., Biteau, N., Franconi, J.-M., Boshart, M., Baltz, T., Bringaud, F. (2005). A Mitochondrial NADH-dependent Fumarate Reductase Involved in the Production of Succinate Excreted by Procyclic Trypanosoma brucei. J. Biol. Chem. 280: 16559-16570 [Abstract] [Full Text]  
  • Ziegler, H. L., Hansen, H. S., Staerk, D., Christensen, S. B., Hagerstrand, H., Jaroszewski, J. W. (2004). The Antiparasitic Compound Licochalcone A Is a Potent Echinocytogenic Agent That Modifies the Erythrocyte Membrane in the Concentration Range Where Antiplasmodial Activity Is Observed. Antimicrob. Agents Chemother. 48: 4067-4071 [Abstract] [Full Text]  
  • Go, M.-L., Liu, M., Wilairat, P., Rosenthal, P. J., Saliba, K. J., Kirk, K. (2004). Antiplasmodial Chalcones Inhibit Sorbitol-Induced Hemolysis of Plasmodium falciparum-Infected Erythrocytes. Antimicrob. Agents Chemother. 48: 3241-3245 [Abstract] [Full Text]  
  • Luque-Ortega, J. R., Martinez, S., Saugar, J. M., Izquierdo, L. R., Abad, T., Luis, J. G., Pinero, J., Valladares, B., Rivas, L. (2004). Fungus-Elicited Metabolites from Plants as an Enriched Source for New Leishmanicidal Agents: Antifungal Phenyl-Phenalenone Phytoalexins from the Banana Plant (Musa acuminata) Target Mitochondria of Leishmania donovani Promastigotes. Antimicrob. Agents Chemother. 48: 1534-1540 [Abstract] [Full Text]  
  • Lunardi, F., Guzela, M., Rodrigues, A. T., Correa, R., Eger-Mangrich, I., Steindel, M., Grisard, E. C., Assreuy, J., Calixto, J. B., Santos, A. R. S. (2003). Trypanocidal and Leishmanicidal Properties of Substitution-Containing Chalcones. Antimicrob. Agents Chemother. 47: 1449-1451 [Abstract] [Full Text]  
  • Besteiro, S., Biran, M., Biteau, N., Coustou, V., Baltz, T., Canioni, P., Bringaud, F. (2002). Succinate Secreted by Trypanosoma brucei Is Produced by a Novel and Unique Glycosomal Enzyme, NADH-dependent Fumarate Reductase. J. Biol. Chem. 277: 38001-38012 [Abstract] [Full Text]  
  • Tsukiyama, R.-I., Katsura, H., Tokuriki, N., Kobayashi, M. (2002). Antibacterial Activity of Licochalcone A against Spore-Forming Bacteria. Antimicrob. Agents Chemother. 46: 1226-1230 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»