JAC Advance Access published online on March 13, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn101
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Original research |
Polyene susceptibility is dependent on nitrogen source in the opportunistic pathogen Candida albicans
1 Department of Pathobiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA 2 Seattle Biomedical Research Institute, Seattle, WA, USA
Received 9 October 2007; returned 20 December 2007; revised 15 February 2008; accepted 18 February 2008
* Correspondence address. Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109-5129, USA. Tel: +1-206-256-7344; Fax: +1-206-256-7229; E-mail: ted.white{at}sbri.org
Objectives: Polyene antifungal drugs, including amphotericin B or nystatin, target ergosterol in the fungal plasma membrane and are used to treat systemic, vaginal and oral fungal infections. In the oral cavity, the available nitrogen sources are primarily in the form of proteins, which are poor nitrogen sources. This study evaluates the effect of protein as a nitrogen source on drug susceptibilities.
Methods: Candida albicans was grown in protein [bovine serum albumin (BSA) or casein (CSN)] as a sole nitrogen source, in ammonium sulphate (AS) as a nitrogen source, or in both protein and AS.
Results: Cells grown in BSA or CSN were 4- to 16-fold less susceptible to amphotericin B and nystatin than those grown in AS. Similar results were observed for cycloheximide, but not for fluconazole or caspofungin, and were observed for many C. albicans clinical isolates. The results were observed in two different media, and in broth and on agar. Cells grown under these nitrogen-poor conditions have a reduction in ergosterol sterol levels and a reduction in overall sterol synthesis. Quantitative real-time reverse transcription–polymerase chain reaction analysis shows that some genes involved in sterol biosynthesis are induced under nitrogen-limiting conditions, consistent with the lower sterol levels.
Conclusions: The results demonstrate that nitrogen source has a significant effect on polyene susceptibilities. As these nitrogen-limiting conditions mimic oral nitrogen availability, they suggest that in vitro polyene susceptibilities may overestimate the in vivo susceptibilities to polyene drugs in the mouth.
Key Words: amphotericin B , ergosterol , sterol , secreted aspartyl proteinase