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Antimicrobial Agents and Chemotherapy, January 2001, p. 223-228, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.223-228.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Unusual Susceptibility of a Multidrug-Resistant Yeast Strain to Peptidic Antifungals

Sawomir Milewski,^1,* Fiorenzo Mignini,² Rajendra Prasad,³ and Edward Borowski¹

Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdask, Gdask, Poland¹; Department of Cellular, Molecular and Animal Biology, University of Camerino, Camerino, Italy²; and School of Life Sciences, Jawaharlal Nehru University, New Delhi, India³

Received 24 May 2000/Returned for modification 10 July 2000/Accepted 23 October 2000

The susceptibility of Saccharomyces cerevisiae JG436 multidrug transporter deletion mutant, pdr5, to several antifungal agents was compared to that of JG436-derived JGCDR1 and JGCaMDR1 transformants, harboring the CDR1 and CaMDR1 genes, encoding the main drug-extruding membrane proteins of Candida albicans. The JGCDR1 and JGCaMDR1 yeasts demonstrated markedly diminished susceptibility to the azole antifungals, terbinafine and cycloheximide, while that to amphotericin B was unchanged. Surprisingly, JGCDR1 but not JGCaMDR1 cells showed enhanced susceptibility to peptidic antifungals, rationally designed compounds containing inhibitors of glucosamine-6-phosphate synthase. It was found that these antifungal oligopeptides, as well as model oligopeptides built of proteinogenic amino acids, were not effluxed from JGCDR1 cells. Moreover, they were taken up by these cells at rates two to three times higher than by JG436. The tested oligopeptides were rapidly cleaved to constitutive amino acids by cytoplasmic peptidases. Studies on the mechanism of the observed phenomenon suggested that an additive proton motive force generated by Cdr1p stimulated uptake of oligopeptides into JGCDR1 cells, thus giving rise to the higher antifungal activity of FMDP [N³-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid]-peptides.

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^* Corresponding author. Mailing address: Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdask, 11/12 Narutowicza St., 80-952 Gdask, Poland. Phone: 48-58-3472107. Fax: 48-58-3472694. E-mail: milewski{at}altis.chem.pg.gda.pl.

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Antimicrobial Agents and Chemotherapy, January 2001, p. 223-228, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.223-228.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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