Altered plasmodial surface anion channel activity and in vitro resistance to permeating antimalarial compounds.
Erythrocytes infected with malaria parasites have increased permeability to various solutes. These changes may be mediated by an unusual small conductance ion channel known as the plasmodial surface anion channel (PSAC). While channel activity benefits the parasite by permitting nutrient acquisition, it can also be detrimental because water-soluble antimalarials may more readily access their parasite targets via this channel. Recently, two such toxins, blasticidin S and leupeptin, were used to select mutant parasites with altered PSAC activities, suggesting acquired resistance via reduced channel-mediated toxin uptake. Surprisingly, although these toxins have similar structures and charge, we now show that reduced permeability of one does not protect the intracellular parasite from the other. Leupeptin accumulation in the blasticidin S-resistant mutant was relatively preserved, consistent with retained in vitro susceptibility to leupeptin. Subsequent in vitro selection with both toxins generated a double mutant parasite having additional changes in PSAC, implicating an antimalarial resistance mechanism for water-soluble drugs requiring channel-mediated uptake at the erythrocyte membrane. Characterization of these mutants revealed a single conserved channel on each mutant, albeit with distinct gating properties. These findings are consistent with a shared channel that mediates uptake of ions, nutrients and toxins. This channel's gating and selectivity properties can be modified in response to in vitro selective pressure.
Lisk
Godfrey
G
The Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.
Pain
Margaret
M
Sellers
Morgan
M
Gurnev
Philip A
PA
Pillai
Ajay D
AD
Bezrukov
Sergey M
SM
Desai
Sanjay A
SA
D000838:Anions; D000962:Antimalarials / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D004351:Drug Resistance; D004910:Erythrocyte Membrane / Q000378:metabolism; D015640:Ion Channel Gating; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism
D000838:Anions; D000962:Antimalarials; D007473:Ion Channels
Antimicrob Agents Chemother. 2009 Dec;53(12):4968-78
19752273
Mol Biochem Parasitol. 1983 Jun;8(2):177-90
6348537
Nature. 2000 Aug 31;406(6799):1001-5
10984055
Mol Biochem Parasitol. 2003 Nov;132(1):27-34
14563534
Am J Physiol. 1993 Apr;264(4 Pt 1):C761-82
8476015
PLoS Pathog. 2008 Jun 13;4(6):e1000084
18551176
Antimicrob Agents Chemother. 2008 Jul;52(7):2346-54
18443109
Trends Biochem Sci. 1991 Apr;16(4):150-3
1877091
Mol Biochem Parasitol. 1985 Mar;14(3):313-22
3887158
Mol Cell Biol. 1997 Jun;17(6):3373-81
9154836
J Virol. 1979 Jan;29(1):114-22
219211
J Biol Chem. 2004 Mar 12;279(11):10316-22
14679190
FASEB J. 2006 Jan;20(1):133-5
16267125
Nature. 2006 Sep 14;443(7108):226-9
16921385
Blood. 2004 Dec 15;104(13):4279-86
15319279
Biophys J. 2005 Mar;88(3):L17-9
15626697
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):417-21
18184817
Int J Parasitol. 2007 Mar;37(3-4):317-27
17207486
Eukaryot Cell. 2005 Dec;4(12):2153-9
16339732
Nat Rev Microbiol. 2009 May;7(5):341-54
19369950
Biophys J. 1987 Dec;52(6):1047-54
2447968
Curr Genet. 1985;9(2):179-81
3916720
J Biol Chem. 2004 Aug 20;279(34):35236-41
15192087
Transfus Clin Biol. 2008 Feb-Mar;15(1-2):72-81
18501653
J Clin Invest. 2008 May;118(5):1867-76
18398509
Biophys J. 1987 Dec;52(6):979-88
2447974
Int J Parasitol. 2007 Apr;37(5):475-82
17292372
Cell Microbiol. 2007 Apr;9(4):851-60
17087736
Mol Pharmacol. 2007 May;71(5):1241-50
17287402
Biochim Biophys Acta. 2000 Jan 15;1463(1):88-98
10631297
Mol Microbiol. 2009 Apr;72(2):459-69
19320831
J Med Chem. 2009 Feb 12;52(3):852-7
19128015
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8716-20
10411941
Biol Chem. 2002 May;383(5):843-7
12108550
J Biochem. 1965 May;57(5):667-77
4953866
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):1063-8
17213308
PLoS Pathog. 2008 Feb 8;4(2):e19
18248092
J Membr Biol. 2008 Nov-Dec;226(1-3):27-34
19050955
J Biol Chem. 1994 Feb 4;269(5):3339-47
8106373
Mol Biochem Parasitol. 1985 Jun;16(1):75-83
3929085
Phys Rev Lett. 2002 Oct 7;89(15):158101
12366027
Methods Mol Biol. 1996;53:17-38
8924979
J Membr Biol. 2002 May 15;187(2):147-56
12029371
Phys Rev Lett. 2000 Jul 3;85(1):202-5
10991194
Mol Biochem Parasitol. 1989 Mar 1;33(2):151-8
2657420
Annu Rev Microbiol. 1982;36:259-84
6816136
Methods Mol Biol. 2004;270:263-76
15153633
Mol Pharmacol. 2010 May;77(5):724-33
20101003
Acta Leiden. 1991;60(1):93-9
1820719
Biophys J. 2003 Jan;84(1):116-23
12524269
Malar J. 2008 May 20;7:86
18492282
Nanomedicine. 2005 Mar;1(1):58-66
17292059
Mol Pharmacol. 2005 Jul;68(1):34-40
15843600
J Clin Invest. 1988 Nov;82(5):1560-6
3053784