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J. Biol. Chem., Vol. 280, Issue 17, 16861-16867, April 29, 2005

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Plasmodial Surface Anion Channel-independent Phloridzin Resistance in Plasmodium falciparum^*

Sanjay A. Desai, Abdulnaser Alkhalil, Myungsa Kang, Umar Ashfaq, and My-Le Nguyen

From the Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Bethesda, Maryland 20892

The plasmodial surface anion channel (PSAC) is an unusual ion channel induced on the human red blood cell membrane after infection with the malaria parasite, Plasmodium falciparum. Because PSAC is permeant to small metabolic precursors essential for parasite growth and is present on red blood cells infected with geographically divergent parasite isolates, it may be an ideal target for future antimalarial development. Here, we used chemically induced mutagenesis and known PSAC antagonists that inhibit in vitro parasite growth to examine whether resistance mutations in PSAC can be readily induced. Stable mutants resistant to phloridzin were generated and selected within 3 weeks after treatment with 1-methyl-3-nitro-1-nitrosoguanidine. These mutants were evaluated with osmotic lysis and electrophysiological transport assays, which indicate that PSAC inhibition by phloridzin is complex with at least two different modes of inhibition. Mutants resistant to the growth inhibitory effects of phloridzin expressed PSAC activity indistinguishable from that on sensitive parasites, indicating selection of resistance via mutations in one or more other parasite targets. Failure to induce mutations in PSAC activity is consistent with a highly constrained channel protein less susceptible to resistance mutations; whether this protein is parasite- or host-encoded remains to be determined.

Received for publication, December 28, 2004 , and in revised form, February 7, 2005.

^* This work was supported by intramural funds from the NIAID, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Laboratory of Malaria and Vector Research, NIAID/National Institutes of Health, Rm. 3W-01, 12735 Twinbrook Pkwy., Rockville, MD 20852-8132. Tel.: 301-435-7552; Fax: 301-402-0079; E-mail: sdesai{at}niaid.nih.gov.

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