Antifungals and C albicans

A huge number of studies have focussed on transcript profiling of gene expression changes occurring in response to anti-infective or antifungal treatment/exposure (De Backer et al., 2001; Kontoyiannis & May, 2001; Barker & Rogers, 2005; Copping et al., 2005; Lee et al., 2005; Lepak et al., 2006; Neuhof et al., 2006), as well as studying strains that have become resistant to antifungals (Rogers & Barker, 2002; Barker et al., 2004; Xu et al., 2006). These studies demonstrate that treatment with different antifungal agent classes induce different transcriptional responses (Table 5.4).

The antifungal glycosylated lipopeptide Hassallidin A (Neuhof et al., 2005) was found to induce metabolic and mitotic genes (Neuhof et al., 2006). In addition, both fluconazole and caspofungin were found to modulate expression of SAP2 and SAP9 (Copping et al., 2005). The anti-infective agent ciclopirox olamine, used to treat superficial mycoses, thought to work as an iron chelator, was found to induce genes involved in iron uptake as well as virulence-associated genes in C. albicans (Niewerth et al., 2003; Lee et al., 2005).

Azole-resistant strains, either experimentally or clinically induced, were found to have upregulated genes involved in cell stress (DDR48 and RTA2), as well as ergosterol biosynthetic genes (Rogers & Barker, 2002; Barker et al., 2004; Karababa et al., 2004). CDR1 and CDR2, previously demonstrated to be associated with azole resistance, have also been found to be upregulated in azole resistant strains when compared with azole sensitive strains (Rogers & Barker, 2002; Karababa et al., 2004; Xu et al., 2006). The CDR genes and some of the stress genes

Table 5.4 C. albicans genes regulated in response to antifungal treatment found by transcript profiling experiments

Genes regulated in C. albicans Antifungal drug during exposure to antifungal References

Table 5.4 C. albicans genes regulated in response to antifungal treatment found by transcript profiling experiments

Genes regulated in C. albicans Antifungal drug during exposure to antifungal References

Amphotericin B

Small molecule (ion)

transport genes Stress genes (including oxidative stress genes) Lipid, fatty acid and sterol synthesis genes

Liu et al. (2005)

Azoles

Lipid, fatty acid and sterol synthesis genes

De Backer et al. (2001)

Small molecule transport

Liu et al. (2005)

Carbohydrate metabolism

Lepak et al. (2006)

Stress genes

Echinocandins

Cell wall maintenance genes Small molecule transport Stress genes

Lipid, fatty acid and sterol synthesis genes

Liu et al. (2005)

5-flucytosine

Protein synthesis Purine/ pyrimidine synthesis genes

Liu et al. (2005)

Hassallidin A

Metabolic genes Mitotic genes

Neuhof et al. (2006)

induced during antifungal treatment contain DRE elements in their promoters and have been found to be co-ordinately regulated by the transcription factor Taclp (Coste et al., 2004). It is also interesting to note that among C. albicans isolates changes in transcription of different groups of genes were associated with drug resistance (Xu et al., 2006).

Proteomic analysis was carried out to examine the changes that occur in response to treatment with either azoles or echinocandins (Bruneau et al., 2003). The response to azoles could be clearly differentiated from the response to echinocand-ins, and the authors suggest that proteomic analyses may provide clues to the mechanism of action for drugs of unknown action. Azole resistance-associated proteins include Grp2p, Ifdlp, Ifd4p, Ifd5p, and Erg10p, a protein involved in the ergosterol biosynthesis pathway (Hooshdaran et al., 2004).

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