Enhanced susceptibility to antifungal oligopeptides in yeast strains overexpressing ABC multidrug efflux pumps.
The susceptibility to several oligopeptide and amino acid antifungals of a Saccharomyces cerevisiae strain carrying multiple deletions in yeast multidrug resistance genes was compared to transformants containing the CDR1, CDR2, or MDR1 genes that encode the major Candida albicans drug efflux pumps. Recombinant yeast strains overexpressing Cdr1p and Cdr2p showed enhanced susceptibilities to all tested oligopeptide antifungals. The enhanced susceptibilities of multidrug-resistant yeast strains to oligopeptide antifungals corresponded to higher rates of oligopeptide uptake. Yeast cells overexpressing Cdr1p or Cdr2p effluxed protons at higher rates than the reference cells lacking these ABC transporters. An increased plasma membrane electrochemical gradient caused by the functional overexpression of Cdr1p or Cdr2p appeared to increase cellular susceptibility to oligopeptide antifungals by stimulating their uptake via oligopeptide permeases.
Wakiec
Roland
R
Department of Pharmaceutical Technology & Biochemistry, Gdańsk University of Technology, Gdańsk, Poland.
Gabriel
Iwona
I
Prasad
Rajendra
R
Becker
Jeffrey M
JM
Payne
John W
JW
Milewski
Slawomir
S
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D025141:Drug Resistance, Fungal / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005800:Genes, Fungal; D019450:Genes, MDR; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D009842:Oligopeptides; D011994:Recombinant Proteins
J Biol Chem. 1988 Dec 5;263(34):18118-22
3056938
Biochem J. 1978 Apr 15;172(1):15-22
26338
Biochem J. 2006 Oct 1;399(1):1-7
16956326
Clin Microbiol Rev. 2007 Jan;20(1):133-63
17223626
Clin Infect Dis. 2003 Nov 1;37(9):1172-7
14557960
J Med Chem. 1983 Dec;26(12):1725-9
6644741
Biochim Biophys Acta. 1997 Mar 14;1331(1):41-79
9325435
Antimicrob Agents Chemother. 1991 Jan;35(1):36-43
1901701
Curr Genet. 1995 Mar;27(4):320-9
7614555
Antimicrob Agents Chemother. 1976 Sep;10(3):483-90
791103
J Med Chem. 1990 Jan;33(1):132-5
2104933
Mol Cell Biol. 1994 Jan;14(1):104-15
8264579
Antimicrob Agents Chemother. 1985 Oct;28(4):494-9
3907495
Biochemistry. 1999 Mar 30;38(13):4214-26
10194338
Lancet. 2005 Sep 17-23;366(9490):1013-25
16168784
Biochem Biophys Res Commun. 1993 Feb 15;190(3):1037-44
8439305
Mycoses. 2007 Mar;50(2):109-15
17305773
Yeast. 1998 Apr 30;14(6):535-50
9605504
Clin Infect Dis. 2003 Jan 15;36(Suppl 1):S31-41
12516028
Curr Genet. 1999 Dec;36(6):317-28
10654085
Eur J Clin Microbiol Infect Dis. 2002 Nov;21(11):767-74
12461585
J Bacteriol. 1984 Dec;160(3):884-8
6389515
Nature. 1986 Feb 20-26;319(6055):689-93
3005867
Mol Membr Biol. 2001 Jan-Mar;18(1):105-12
11396605
J Med Chem. 1980 Aug;23(8):913-8
6995613
J Biol Chem. 1979 Apr 25;254(8):2928-34
155060
J Gen Microbiol. 1986 Aug;132(8):2147-53
3540196
Antimicrob Agents Chemother. 1996 Dec;40(12):2835-41
9124851
Curr Genet. 1998 Sep;34(3):192-9
9745021
Mol Microbiol. 2006 May;60(3):795-812
16629678
Int Rev Cytol. 2005;242:215-48
15598470
Antonie Van Leeuwenhoek. 2001 Sep;79(3-4):297-309
11816973
J Biol Chem. 2006 Aug 11;281(32):22453-63
16720580
J Biol Chem. 1998 May 15;273(20):12612-22
9575223
Antimicrob Agents Chemother. 2001 Jan;45(1):223-8
11120970
J Biotechnol. 1995 Jan 15;38(2):165-72
7765807
J Gen Microbiol. 1992 Nov;138(11):2353-62
1479355
Int J Biochem. 1992;24(1):145-9
1582527
Microbiology (Reading). 2003 Sep;149(Pt 9):2597-2608
12949183
Mycoses. 1999;42(7-8):453-8
10546486
J Exp Biol. 2000 Jan;203(Pt 1):155-60
10600684
Yeast. 2002 Mar 15;19(4):303-18
11870854
Antimicrob Agents Chemother. 1998 Dec;42(12):3065-72
9835492