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 Choubey, V.
Right arrow Articles by Bandyopadhyay, U.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Choubey, V.
Right arrow Articles by Bandyopadhyay, U.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, February 2007, p. 696-706, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.00919-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism{triangledown}

Vinay Choubey,1 Pallab Maity,1,{dagger} Mithu Guha,1,{dagger} Sanjay Kumar,1 Kumkum Srivastava,2 Sunil Kumar Puri,2 and Uday Bandyopadhyay1*

Division of Drug Target Discovery and Development,1 Division of Parasitology, Central Drug Research Institute, Chatter Manzil Palace, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India2

Received 25 July 2006/ Returned for modification 7 September 2006/ Accepted 22 November 2006

Choline kinase is the first enzyme in the Kennedy pathway (CDP-choline pathway) for the biosynthesis of the most essential phospholipid, phosphatidylcholine, in Plasmodium falciparum. In addition, choline kinase also plays a pivotal role in trapping essential polar head group choline inside the malaria parasite. Recently, Plasmodium falciparum choline kinase (PfCK) has been cloned, overexpressed, and purified. However, the function of this enzyme in parasite growth and survival has not been evaluated owing to the lack of a suitable inhibitor. Purified recombinant PfCK enabled us to identify an inhibitor of PfCK, hexadecyltrimethylammonium bromide (HDTAB), which has a very close structural resemblance to hexadecylphosphocholine (miltefosin), the well-known antiproliferative and antileishmanial drug. HDTAB inhibited PfCK in a dose-dependent manner and offered very potent antimalarial activity in vitro against Plasmodium falciparum. Moreover, HDTAB exhibited profound antimalarial activity in vivo against the rodent malaria parasite Plasmodium yoelii (N-67 strain). Interestingly, parasites at the trophozoite and schizont stages were found to be particularly sensitive to HDTAB. The stage-specific antimalarial effect of HDTAB correlated well with the expression pattern of PfCK in P. falciparum, which was observed by reverse transcription-PCR and immunofluorescence microscopy. Furthermore, the antimalarial activity of HDTAB paralleled the decrease in phosphatidylcholine content, which was found to correlate with the decreased phosphocholine generation. These results suggest that inhibition of choline kinase by HDTAB leads to decreased phosphocholine, which in turn causes a decrease in phosphatidylcholine biosynthesis, resulting in death of the parasite.

* Corresponding author. Present address: Division of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata-700032, India. Phone: 91 33 4733491. Fax: 91 33 4730284. E-mail: ubandyo_1964{at}yahoo.com.

{triangledown} Published ahead of print on 4 December 2006.

{dagger} Present address: Division of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, Kolkata-700032, India.

Antimicrobial Agents and Chemotherapy, February 2007, p. 696-706, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.00919-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kumar, S., Das, S. K., Dey, S., Maity, P., Guha, M., Choubey, V., Panda, G., Bandyopadhyay, U. (2008). Antiplasmodial Activity of [(Aryl)arylsulfanylmethyl]Pyridine. Antimicrob. Agents Chemother. 52: 705-715 [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»