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Antimicrobial Agents and Chemotherapy, April 2007, p. 1217-1222, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.00895-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Growth Inhibition of Toxoplasma gondii and Plasmodium falciparum by Nanomolar Concentrations of 1-Hydroxy-2-Dodecyl-4(1H)Quinolone, a High-Affinity Inhibitor of Alternative (Type II) NADH Dehydrogenases

Institute of Medical Microbiology, University of Göttingen, Kreuzbergring 57, Göttingen D-37075, Germany,¹ FB Biologie/Parasitologie, Philipps-Universität Marburg, Karl von Frisch Strasse 8, D-35032 Marburg, Germany²

Received 20 July 2006/ Returned for modification 25 October 2006/ Accepted 3 January 2007

Both apicomplexan parasites Toxoplasma gondii and Plasmodium falciparum lack type I NADH dehydrogenases (complex I) but instead carry alternative (type II) NADH dehydrogenases, which are absent in mammalian cells and are thus considered promising antimicrobial drug targets. The quinolone-like compound 1-hydroxy-2-dodecyl-4(1H)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 rates of P. falciparum and T. gondii in tissue culture. The 50% inhibitory concentration (IC₅₀) of HDQ for T. gondii was determined to be 2.4 ± 0.3 nM with a growth assay based on vacuole sizes and 3.7 ± 1.4 nM with a growth assay based on beta-galactosidase activity. Quantification of the P. falciparum replication rate using a fluorometric assay revealed an IC₅₀ of 14.0 ± 1.9 nM. 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 cytochrome b in complex III, resulted in synergism, with a calculated fractional inhibitory concentration of 0.16 nM. Interference of the mitochondrial ubiquinone/ubiquinol cycle at two different locations thus appears to be a highly effective strategy for inhibiting parasite replication. HDQ and its derivatives, particularly in combination with atovaquone, represent promising compounds with a high potential for antimalarial and antitoxoplasmal therapy.

Published ahead of print on 22 January 2007.