Trends in Molecular Medicine
ReviewMolecular basis of resistance to azole antifungals
Section snippets
Polyenes
Polyenes target ergosterol in fungal membranes. They are fungicidal agents used in short treatment regimens due to associated toxicity, which may account for the low incidence of resistance encountered. Consistent with this mode of action, amphotericin B-resistant Candida strains often have a marked decrease in ergosterol content compared with amphotericin B-susceptible control isolates [1]. Resistance in clinical isolates of Cryptococcus neoformans was also associated with a mutation
Other drugs
Flucytosine, which inhibits cellular DNA and RNA synthesis, is mainly used in combination therapy as Candida was observed to become resistant at high frequency. Flucytosine resistance occurs in C.albicans strains bearing molecular variants of cytosine deaminase, uracil phosphoribosyl-transferase or uridine monophosphate-pyrophosphorylase [5].
Of the other antifungal drugs currently used, terbinafine and amorolfine also target ergosterol biosynthesis [1]. The former inhibits squalene epoxidase
Azole antifungals
Among the different categories of antifungal drugs, the development of azole resistance is the most relevant medical problem. Treatment failures have been observed following the extensive use of fluconazole for the management of Candida infections. In particular, resistance is associated with relapses of oropharyngeal candidiasis in AIDS patients, but azole resistance has also been observed in other settings and for different fungi. The first observations of azole resistance were in patients
Mechanisms of resistance to azoles
Extensive biochemical studies highlighted a significant diversity in the mechanisms conferring resistance to azoles. Since drug resistance can develop as a stepwise process over time, these mechanisms may combine with each other.
Concluding remarks
Genome-wide transcription profiles, obtained by the use of microarrays, can be used to provide insight into the mode of action of an antifungal agent, as well as to characterize the response to perturbation of ergosterol metabolic pathway following exposure to a number of antifungal agents, including azoles and allylamines 39, 40. Indeed, the feasibility of such studies has recently been shown [57].
Finally, novel drug targets are being discovered by examination of the haploinsufficient
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