Clinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance

Abstract

SUMMARY In the past decade, the frequency of diagnosed fungal infections has risen sharply due to several factors, including the increase in the number of immunosuppressed patients resulting from the AIDS epidemic and treatments during and after organ and bone marrow transplants. Linked with the increase in fungal infections is a recent increase in the frequency with which these infections are recalcitrant to standard antifungal therapy. This review summarizes the factors that contribute to antifungal drug resistance on three levels: (i) clinical factors that result in the inability to successfully treat refractory disease; (ii) cellular factors associated with a resistant fungal strain; and (iii) molecular factors that are ultimately responsible for the resistance phenotype in the cell. Many of the clinical factors that contribute to resistance are associated with the immune status of the patient, with the pharmacology of the drugs, or with the degree or type of fungal infection present. At a cellular level, antifungal drug resistance can be the result of replacement of a susceptible strain with a more resistant strain or species or the alteration of an endogenous strain (by mutation or gene expression) to a resistant phenotype. The molecular mechanisms of resistance that have been identified to date in Candida albicans include overexpression of two types of efflux pumps, overexpression or mutation of the target enzyme, and alteration of other enzymes in the same biosynthetic pathway as the target enzyme. Since the study of antifungal drug resistance is relatively new, other factors that may also contribute to resistance are discussed.

Aryloxyacetic esters structurally related to α-Asarone as potential antifungal agents

“…The fact that the lipophilic effect might play a role in facilitating the transport of the drugs through the lipophilic membranes of the yeasts (White et al, 1998) prompted us to choose a series of long and lineal hydrocarbon chains for the partnership alcohols, as well as an aromatic ring substituted by a chlorine atom. In the series of esters 9a-e, a methyl group was introduced at the para position with respect to the acetic ester moiety, conserving the same series of alcohols (Scheme 1).…”

“…However, fungal pathogens acquire resistance, which hampers effective treatment strategies (Prasad et al, 2002). These mainly opportunistic fungi acquire resistance during prophylaxis, intermittent or monotherapy, for instance, in the case of the resistance of Candida species, Cryptococcus neoformans and the recently accepted species (Kwon-Chung et al, 2002) C. gattii to flucytosine, amphotericin B, and azoles (Kwon-Chung et al, 2002;White et al, 1998;Sterling and Merz, 1998;Vanden Bossche et al, 1998;Pfaller et al, 2004).…”

Determination of thein vitro activity of fluconazole against yeast strains using HPLC

“…Fluconazole resistance mechanisms have been extensively studied and include the following: overexpression of the target protein, overexpression of membrane efflux pumps, alteration in sterol biosynthesis, and mutations of the target protein (Vanden Bossche et al, 1998;White et al, 1998;Lupetti et al, 2002;Smriti et al, 2002;Casalinuovo et al, 2004;Shen et al, 2007). Other possible mechanisms involving modification or degradation of antifungal drugs have not yet been adequately explored (White et al, 1998).…”

“…Other possible mechanisms involving modification or degradation of antifungal drugs have not yet been adequately explored (White et al, 1998). To date, no data correlating altered fluconazole metabolism to resistance have been reported (Ghannoum and Rice, 1999).…”

Estimation of Selection Parameters using Multi-generation Cytonuclear Data

“…They considered a general sampling scheme suitable for both experimental and natural populations first studied by Fisher and Ford (1947). Moreover, this type of sampling schemes will become increasingly important in prospective tests for selection (White et al, 1998) using molecular markers in which a cytoplasmic marker is included as a control.…”