Candida albicans Flu1-Mediated Efflux of Salivary Histatin 5 Reduces Its Cytosolic Concentration and Fungicidal Activity

From the Department of Oral Biology University at Buffalo, Buffalo, New York 14214.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 02/2013; 57(4). DOI: 10.1128/AAC.02295-12
Source: PubMed


Histatin 5 (Hst 5) is a salivary human antimicrobial peptide that is toxic to the opportunistic yeast Candida albicans. Fungicidal activity of Hst 5 requires intracellular translocation and accumulation to a threshold concentration for it to
disrupt cellular processes. Previously, we observed that total cytosolic levels of Hst 5 were gradually reduced from intact
cells, suggesting that C. albicans possesses a transport mechanism for efflux of Hst 5. Since we identified C. albicans polyamine transporters responsible for Hst 5 uptake, we hypothesized that one or more polyamine efflux transporters may be
involved in the efflux of Hst 5. C. albicans FLU1 and TPO2 were found to be the closest homologs of Saccharomyces cerevisiae TPO1, which encodes a major spermidine efflux transporter, indicating that the products of these two genes may be involved in
efflux of Hst 5. We found that flu1Δ/Δ cells, but not tpo2Δ/Δ cells, had significant reductions in their rates of Hst 5 efflux and had significantly higher cytoplasmic Hst 5 and Hst
5 susceptibilities than did the wild type. We also found that flu1Δ/Δ cells had reduced biofilm formation compared to wild-type cells in the presence of Hst 5. Transcriptional levels of FLU1 were not altered over the course of treatment with Hst 5; therefore, Hst 5 is not likely to induce FLU1 gene overexpression as a potential mechanism of resistance. Thus, Flu1, but not Tpo2, mediates efflux of Hst 5 and is responsible
for reduction of its toxicity in C. albicans.


Available from: Sumant Puri
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    • "In Candida species the following four major mechanisms of resistance to azoles have been described. These are active efflux of the drug [31] [32], over expression of the target molecule [33] [34] [35], development of bypass pathway [36] and molecular structural alteration of the target molecule [37]. "
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