Wednesday, January 24, 2007

Effect of High Affinity Inhibitor of Alternative (type II) NADH Dehydrogenases on Toxo

Antimicrob Agents Chemother. 2007 Jan 22; [Epub ahead of print]

Growth inhibition of Toxoplasma gondii and Plasmodium falciparum by Nanomolar Concentrations of HDQ (1-hydroxy-2-dodecyl-4(1H)quinolone): a High Affinity Inhibitor of Alternative (type II) NADH Dehydrogenases.

Saleh A, Friesen J, Baumeister S, Gross U, Bohne W.

Institute of Medical Microbiology, University of Gottingen, Kreuzbergring 57, Gottingen D-37075; Germany; FB Biologie/Parasitologie, Philipps-Universitat Marburg, Karl von Frisch Strasse 8, D-35032 Marburg; Germany.

Both apicomplexan parasites Toxoplasma gondii and Plasmodium falciparum lack type I NADH dehydrogenases (complex I), but instead encode alternative (type II) NADH dehydrogenases, which are absent in mammalian cells and are thus considered as promising antimicrobial drug targets. The quinolone-like compound 1-hydroxy-2-dodecyl-4(1)quinolone (HDQ) was recently described as a high affinity inhibitor of fungal alternative NADH-dehydrogenases in enzymatic assays, probably by interfering with the ubiquinol binding site of the enzyme. We describe here that HDQ effectively inhibits the replication rate of P. falciparum and T. gondii in tissue culture. The IC50 of HDQ was determined for T. gondii at 2.4 +/- 0.3 nM with a growth assay based on vacuole sizes and at 3.7 +/- 1.4 nM with a growth assay based on beta-galactosidase activity. Quantification of P. falciparum replication rate using a fluorometric assay revealed an IC50 of 14.0 nM +/- 1.9. An important feature of the HDQ structure is the length of the alkyl side chain at position 2. Derivatives with alkyl side chains of C6, C8, C12 (HDQ) and C14 all displayed excellent anti-T. gondii activity, while a C5 derivative completely failed to inhibit parasite replication. A combined treatment of T. gondii infected cells with HDQ and the antimalarial agent atovaquone, which blocks the ubiquinol oxidation site of cytochrom b in complex III, resulted in synergism with a calculated FIC of 0.16 nM. An interference of the mitochondrial ubiquinone/ubiquinol cycle at two different locations thus appears to be a highly effective strategy to inhibit parasite replication. HDQ and its derivatives represent particularly in combination with atovaquone promising compounds with high potential for antimalarial and antitoxoplasmal therapy.

PMID: 17242151 [PubMed - as supplied by publisher]


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