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Antimicrobial Agents and Chemotherapy, November 2005, p. 4649-4657, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4649-4657.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Class of Pantothenic Acid Analogs Inhibits Plasmodium falciparum Pantothenate Kinase and Represses the Proliferation of Malaria Parasites{dagger}

Christina Spry,1 Christina L. L. Chai,3,4 Kiaran Kirk,1 and Kevin J. Saliba1,2*

School of Biochemistry and Molecular Biology,1 Medical School,2 Department of Chemistry, The Australian National University, Canberra ACT 0200, Australia,3 Institute of Chemical and Engineering Sciences, 1 Pesek Road, Jurong Island, Singapore 6278334

Received 12 May 2005/ Returned for modification 14 June 2005/ Accepted 22 August 2005

The growth and proliferation of the human malaria parasite Plasmodium falciparum are dependent on the parasite's ability to obtain essential nutrients. One nutrient for which the parasite has an absolute requirement is the water-soluble vitamin pantothenic acid (vitamin B5). In this study, a series of pantothenic acid analogs which retain the 2,4-dihydroxy-3,3-dimethylbutyramide core of pantothenic acid but deviate in structure from one another and from pantothenic acid in the nature of the substituent attached to the amide nitrogen were synthesized using an efficient single-step synthetic route. Eight of 10 analogs tested inhibited the proliferation of intraerythrocytic P. falciparum parasites in vitro, doing so with 50% inhibitory concentrations between 15 and 200 µM. The compounds were generally selective, inhibiting the proliferation of a human cell line (the Jurkat cell line) only at concentrations severalfold higher than those required for inhibition of parasite growth. It was demonstrated that compounds in this series inhibited the phosphorylation of pantothenic acid by pantothenate kinase, the first step in the parasite's biosynthesis of the essential enzyme cofactor coenzyme A, doing so competitively, with Ki values in the nanomolar range.

* Corresponding author. Mailing address: School of Biochemistry and Molecular Biology, The Australian National University, Canberra ACT 0200, Australia. Phone: 61 2 6125 7549. Fax: 61 2 6125 0313. E-mail: kevin.saliba{at}anu.edu.au.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, November 2005, p. 4649-4657, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4649-4657.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lehane, A. M., Marchetti, R. V., Spry, C., van Schalkwyk, D. A., Teng, R., Kirk, K., Saliba, K. J. (2007). Feedback Inhibition of Pantothenate Kinase Regulates Pantothenol Uptake by the Malaria Parasite. J. Biol. Chem. 282: 25395-25405 [Abstract] [Full Text]  


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