Coordinate control of lipid composition and drug transport activities is required for normal multidrug resistance in fungi

Abstract

Summary Pathogenic fungi present a special problem in the clinic as the range of drugs that can be used to treat these types of infections is limited. This situation is further complicated by the presence of robust inducible gene networks encoding different proteins that confer tolerance to many available antifungal drugs. The transcriptional control of these multidrug resistance systems in several key fungi will be discussed. Experiments in the non-pathogenic Saccharomyces cerevisiae have provided much of our current understanding of the molecular framework on which fungal multidrug resistance is built. More recent studies on the important pathogenic Candida species, Candida albicans and Candida glabrata, have provided new insights into the organization of the multidrug resistance systems in these organisms. We will compare the circuitry of multidrug resistance networks in these three organisms and suggest that, in addition to the well-accepted drug efflux activities, the regulation of membrane composition by multidrug resistance proteins provides an important contribution to the resistant phenotypes observed.

Phytosphingosine-1-Phosphate Is a Signaling Molecule Involved in Miconazole Resistance in Sessile Candida albicans Cells

“…A more rigid structure of the cytoplasmic membranes of both strains after treatment with miconazole was noticed. Changes in the composition of the cytoplasmic membrane due to stress situations were described previously (25). The addition of PHS-1-P to sessile cells of the LCB4/lcb4 mutant had neither a direct nor an indirect effect on the fluidity of the cytoplasmic membrane, indicating that changes in membrane fluidity are not responsible for this protective effect.…”

Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac

“…However, in a plate reader assay, the minimum concentration of diclofenac that completely inhibited growth for 12 h ranged from approximately 75 M (⌬pdr5 strain) to 150 M (WT) and 500 M (PDR5-overexpressing strain) (data not shown). The relatively small differences in these concentrations could indicate that Pdr5p does not actively transport diclofenac but rather indirectly affects diclofenac toxicity via an altered membrane composition (40). Regardless of the exact role of Pdr5p, the growth and survival data at 100 M diclofenac clearly show the importance of Pdr5p dosage in diclofenac tolerance.…”

“…4 and 5). This may be due either to direct transport of diclofenac by Pdr5p or to secondary effects of Pdr5p deletion or overexpression (40). Interestingly, a murine homolog of Pdr5p, BCRP1 (ABCG2), can efficiently transport diclofenac in vitro (24).…”

Mitochondrial Sorting and Assembly Machinery Subunit Sam37 in Candida albicans: Insight into the Roles of Mitochondria in Fitness, Cell Wall Integrity, and Virulence

“…Specific mitochondrial mutations in C. albicans, Candida glabrata, and S. cerevisiae lead to either resistance or hypersensitivity to antifungal drugs that target cell membranes, such as the azoles and the polyenes (9,10,15,16,23,24,36,(62)(63)(64)67). In particular, loss of mtDNA is known to lead to drug resistance, including resistance to the azole class of antifungal drugs (15,26,27,36,62,63,66; reviewed in reference 64). To address how deletion of SAM37 and the associated mitochondrial phenotypes affected drug tolerance in C. albicans, we tested the sensitivity of the C. albicans sam37⌬⌬ mutant to the azole drug fluconazole, as well as to the polyene amphotericin B, by determining the MIC and the minimum fungicidal concentration (MFC) ( Table 2).…”