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Antimicrobial Agents and Chemotherapy, January 2005, p. 57-70, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.57-70.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Surface-Active Fungicidal D-Peptide Inhibitors of the Plasma Membrane Proton Pump That Block Azole Resistance

Brian C. Monk,1* Kyoko Niimi,1 Susan Lin,1 Allison Knight,1 Thomas B. Kardos,1 Richard D. Cannon,1 Rekha Parshot,2 Amanda King,2 David Lun,2 and David R. K. Harding2

Molecular Microbiology Laboratory, Department of Oral Sciences, School of Dentistry, University of Otago, Dunedin,1 Centre for Separation Science, Institute for Fundamental Sciences, Massey University, Palmerston North, New Zealand2

Received 29 June 2004/ Returned for modification 8 August 2004/ Accepted 16 September 2004

A 1.8-million-member D-octapeptide combinatorial library was constructed in which each member comprised a diversity-containing N-terminal pentapeptide and a C-terminal amidated triarginine motif. The C-terminal motif concentrated the library members at the fungal cell surface. A primary screen for inhibitors of Saccharomyces cerevisiae and Candida albicans growth, together with an in vitro secondary screen with the S. cerevisiae plasma membrane ATPase (Pma1p) as a target, identified the antifungal D-octapeptide BM0 (D-NH2-RFWWFRRR-CONH2). Optimization of BM0 led to the construction of BM2 (D-NH2-RRRFWWFRRR-CONH2), which had broad-spectrum fungicidal activity against S. cerevisiae, Candida species, and Cryptococcus neoformans; bound strongly to the surfaces of fungal cells; inhibited the physiological activity of Pma1p; and appeared to target Pma1p, with 50% inhibitory concentrations in the range of 0.5 to 2.5 µM. At sub-MICs (<5 µM), BM2 chemosensitized to fluconazole (FLC) S. cerevisiae strains functionally hyperexpressing fungal lanosterol 14{alpha}-demethylase and resistance-conferring transporters of azole drugs. BM2 chemosensitized to FLC some FLC-resistant clinical isolates of C. albicans and C. dubliniensis and chemosensitized to itraconazole clinical isolates of C. krusei that are intrinsically resistant to FLC. The growth-inhibitory concentrations of BM2 did not cause fungal cell permeabilization, significant hemolysis of red blood cells, or the death of cultured HEp-2 epithelial cells. BM2 represents a novel class of broad-spectrum, surface-active, Pma1p-targeting fungicides which increases the potencies of azole drugs and circumvents azole resistance.

* Corresponding author. Mailing address: Molecular Microbiology Laboratory, Department of Oral Sciences, School of Dentistry, University of Otago, P.O. Box 647, Dunedin 9001, New Zealand. Phone: 64 3 479 7099. Fax: 64 3 479 7078. E-mail: brian.monk{at}stonebow.otago.ac.nz.

Antimicrobial Agents and Chemotherapy, January 2005, p. 57-70, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.57-70.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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