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Antimicrobial Agents and Chemotherapy, January 2000, p. 14-18, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Effects of Atovaquone and Diospyrin-Based Drugs on Ubiquinone Biosynthesis in Pneumocystis carinii Organisms

Edna S. Kaneshiro,1,* Donggeun Sul,1 and Banasri Hazra2

Department of Biological Sciences, University of Cincinnati, Cincinnati, Ohio 45221,1 and Department of Pharmacy, Jadavpur University, Calcutta 700-032, India2

Received 8 March 1999/Returned for modification 21 September 1999/Accepted 8 October 1999

The naphthoquinone atovaquone is effective against Plasmodium and Pneumocystis carinii carinii. In Plasmodium, the primary mechanism of drug action is an irreversible binding to the mitochondrial cytochrome bc1 complex as an analog of ubiquinone. Blockage of the electron transport chain ultimately inhibits de novo pyrimidine biosynthesis since dihydroorotate dehydrogenase, a key enzyme in pyrimidine biosynthesis, is unable to transfer electrons to ubiquinone. In the present study, the effect of atovaquone was examined on Pneumocystis carinii carinii coenzyme Q biosynthesis (rather than electron transport and respiration) by measuring its effect on the incorporation of radiolabeled p-hydroxybenzoate into ubiquinone in vitro. A triphasic dose-response was observed, with inhibition at 10 nM and then stimulation up to 0.2 µM, followed by inhibition at 1 µM. Since other naphthoquinone drugs may also act as analogs of ubiquinone, diospyrin and two of its derivatives were also tested for their effects on ubiquinone biosynthesis in P. carinii carinii. In contrast to atovaquone, these drugs did not inhibit the incorporation of p-hydroxybenzoate into P. carinii carinii ubiquinone.

* Corresponding author. Mailing address: Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45221-0006. Phone: (513) 556-9712. Fax: (513) 556-5280. E-mail: Edna.Kaneshiro{at}uc.edu.

Antimicrobial Agents and Chemotherapy, January 2000, p. 14-18, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Basselin, M., Hunt, S. M., Abdala-Valencia, H., Kaneshiro, E. S. (2005). Ubiquinone Synthesis in Mitochondrial and Microsomal Subcellular Fractions of Pneumocystis spp.: Differential Sensitivities to Atovaquone. Eukaryot Cell 4: 1483-1492 [Abstract] [Full Text]  
  • Tazi, J., Bakkour, N., Soret, J., Zekri, L., Hazra, B., Laine, W., Baldeyrou, B., Lansiaux, A., Bailly, C. (2005). Selective Inhibition of Topoisomerase I and Various Steps of Spliceosome Assembly by Diospyrin Derivatives. Mol. Pharmacol. 67: 1186-1194 [Abstract] [Full Text]  
  • Cushion, M. T., Collins, M., Hazra, B., Kaneshiro, E. S. (2000). Effects of Atovaquone and Diospyrin-Based Drugs on the Cellular ATP of Pneumocystis carinii f. sp. carinii. Antimicrob. Agents Chemother. 44: 713-719 [Abstract] [Full Text]  


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