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Antimicrobial Agents and Chemotherapy, January 2004, p. 313-318, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.313-318.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Pyridines and Pyrimidines Mediating Activity against an Efflux-Negative Strain of Candida albicans through Putative Inhibition of Lanosterol Demethylase

Ed T. Buurman,1* April E. Blodgett,1 Kenneth G. Hull,2 and Daniel Carcanague2

Department of Microbiology,1 Department of Chemistry, AstraZeneca R&D Boston, Waltham, Massachusetts 024512

Received 21 July 2003/ Returned for modification 2 September 2003/ Accepted 8 October 2003

The first step in ergosterol biosynthesis in Saccharomyces cerevisiae consists of the condensation of two acetyl coenzyme A (acetyl-CoA) moieties by acetoacetyl-CoA thiolase, encoded by ERG10. The inhibition of the sterol pathway results in feedback activation of ERG10 transcription. A cell-based reporter assay, in which increased ERG10 transcription results in elevated specific ß-galactosidase activity, was used to find novel inhibitors of ergosterol biosynthesis that could serve as chemical starting points for the development of novel antifungal agents. A class of pyridines and pyrimidines identified in this way had no detectable activity against the major fungal pathogen Candida albicans (MICs > 64 µg · ml-1). However, a strain of C. albicans lacking the Cdr1p and Cdr2p efflux pumps was sensitive to the compounds (with MICs ranging from 2 to 64 µg · ml-1), suggesting that they are efficiently removed from wild-type cells. Quantitative analysis of sterol intermediates that accumulated during growth inhibition revealed the accumulation of lanosterol at the expense of ergosterol. Furthermore, a clear correlation was found between the 50% inhibitory concentration at which the sterol profile was altered and the antifungal activity, measured as the MIC. This finding strongly suggests that the inhibition of growth was caused by a reduction in ergosterol synthesis. The compounds described here are a novel class of antifungal pyridines and pyrimidines and the first pyri(mi)dines to be shown to putatively mediate their antifungal activity against C. albicans via lanosterol demethylase.

* Corresponding author. Mailing address: AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451. Phone: (781) 839-4592. Fax: (781) 839-4800. E-mail: ed.buurman{at}astrazeneca.com.

Antimicrobial Agents and Chemotherapy, January 2004, p. 313-318, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.313-318.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Buurman, E. T., Andrews, B., Blodgett, A. E., Chavda, J. S., Schnell, N. F. (2005). Utilization of Target-Specific, Hypersensitive Strains of Saccharomyces cerevisiae To Determine the Mode of Action of Antifungal Compounds. Antimicrob. Agents Chemother. 49: 2558-2560 [Abstract] [Full Text]  


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