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 Google Scholar
Google Scholar
Right arrow Articles by Lisk, G.
Right arrow Articles by Desai, S. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lisk, G.
Right arrow Articles by Desai, S. A.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 2008, p. 2346-2354, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.00057-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Changes in the Plasmodial Surface Anion Channel Reduce Leupeptin Uptake and Can Confer Drug Resistance in Plasmodium falciparum-Infected Erythrocytes{triangledown}

Godfrey Lisk,1 Margaret Pain,1 Ilya Y. Gluzman,3 Shivkumar Kambhampati,1 Tetsuya Furuya,1 Xin-zhuan Su,1 Michael P. Fay,2 Daniel E. Goldberg,3 and Sanjay A. Desai1*

Laboratory of Malaria and Vector Research,1 Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892,2 Howard Hughes Medical Institute, Departments of Molecular Microbiology and Medicine, Washington University, St. Louis, Missouri3

Received 14 January 2008/ Returned for modification 8 March 2008/ Accepted 19 April 2008

Cysteine protease inhibitors kill malaria parasites and are being pursued for development as antimalarial agents. Because they have multiple targets within bloodstream-stage parasites, workers have assumed that resistance to these inhibitors would not be acquired easily. In the present study, we used in vitro selection to generate a parasite resistant to growth inhibition by leupeptin, a broad-profile cysteine and serine protease inhibitor. Resistance was not associated with upregulation of cysteine protease activity, reduced leupeptin sensitivity of this activity, or expression level changes for putative cysteine or serine proteases in the parasite genome. Instead, it was associated with marked changes in the plasmodial surface anion channel (PSAC), an ion channel on infected erythrocytes that functions in nutrient and bulky organic solute uptake. Osmotic fragility measurements, electrophysiological recordings, and leupeptin uptake studies revealed selective reductions in organic solute permeability via PSAC, altered single-channel gating, and reduced inhibitor affinity. These changes yielded significantly reduced leupeptin uptake and could fully account for the acquired resistance. PSAC represents a novel route for the uptake of bulky hydrophilic compounds acting against intraerythrocytic parasite targets. Drug development based on such compounds should proceed cautiously in light of possible resistance development though the selection of PSAC mutants.

* Corresponding author. Mailing address: Laboratory of Malaria and Vector Research, NIAID, NIH, Room 3W-01, 12735 Twinbrook Parkway, Rockville, MD 20852-8132. Phone: (301) 435-7552. Fax: (301) 402-2207. E-mail: sdesai{at}niaid.nih.gov

{triangledown} Published ahead of print on 28 April 2008.

Antimicrobial Agents and Chemotherapy, July 2008, p. 2346-2354, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.00057-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»