Antifungal resistance and new strategies to control fungal infections

Abstract

Despite improvement of antifungal therapies over the last 30 years, the phenomenon of antifungal resistance is still of major concern in clinical practice. In the last 10 years the molecular mechanisms underlying this phenomenon were extensively unraveled. In this paper, after a brief overview of currently available antifungals, molecular mechanisms of antifungal resistance will be detailed. It appears that major mechanisms of resistance are essential due to the deregulation of antifungal resistance effector genes. This deregulation is a consequence of point mutations occurring in transcriptional regulators of these effector genes. Resistance can also follow the emergence of point mutations directly in the genes coding antifungal targets. In addition we further describe new strategies currently undertaken to discover alternative therapy targets and antifungals. Identification of new antifungals is essentially achieved by the screening of natural or synthetic chemical compound collections. Discovery of new putative antifungal targets is performed through genome-wide approaches for a better understanding of the human pathogenic fungi biology.

Figure 1

Chemical structures of cytosine (a) and of two fluoropyrimidines, 5-fluorocytosine (b), and 5-fluorouracil (c).

Figure 2

Intracellular metabolization and action mode of 5-FC in S. cerevisiae, adapted from [11]. In bold are indicated gene names of the respective enzymes. 5-FC: 5-fluorocytosine; 5-FU: 5-fluorouracil; 5-FUMP: 5-fluorouridine monophosphate; 5-FUTP: 5-fluorouridine triphosphate; 5-FdUMP: 5-fluoro deoxyribouridine monophosphate.

Figure 3

Chemical structures of amphotericin B (a), nystatin (b), and natamycin (c), three main polyene drugs.

Figure 4

3D model of pore formed by amphotericin B into lipid bilayer of the fungal plasma membrane, adapted from Baginski et al. [29]. Amphotericin B: white (H), green (C), red (O), and blue (N); ergosterol: pink.

Figure 5

Chemical structures of the main azole antifungals, four imidazoles: clotrimazole (a), econazole (b), miconazole (c), and ketoconazole (d), two triazoles: itraconazole (e) and fluconazole (f), and three new generation triazoles: voriconazole (g), posaconazole (h), and ravuconazole (i).

Figure 6

Chemical structure of the three echinocandins used in clinical practice: micafungin (a), caspofungin (b), and anidulafungin (c).

Figure 7

Schematic representation of S. cerevisiae cell wall, adapted from Stone et al. [69].

Figure 8

Mechanisms of resistance to azole compounds in C. albicans.

Figure 9

Point mutations affecting antifungal susceptibility in clinical isolates of C. albicans. Indicated functional domains were determined using either Prosite or Pfam tools. Only mutations which involvement in antifungal resistance was experimentally demonstrated are indicated by a red stick. Hot spot mutations in Erg11 and Fks1 are delimitated by gray boxes (Point mutation localization references: Tac1 [112], Mrr1 [133], Upc2 [134], Erg11 [135], Fks1 [136], Fur1 [137]). Drawings of the proteins were made with Prosite My Domain-Image Creator tool.