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Chapter 25 : Emergence and Evolution of Antifungal Resistance
Category: Fungi and Fungal Pathogenesis; Bacterial Pathogenesis
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The intent of this chapter is to take a broader perspective, extending our understanding of acquired resistance in a few fungi to the problem of intrinsic (primary) resistance throughout the fungal kingdom. In diploid fungi heterozygous mutations associated with antifungal resistance may be dominant or recessive; under selective pressure the latter may undergo mitotic gene conversion to homozygosity. A role for genome instability (chromosome rearrangements or aneuploidy) in antifungal resistance was illustrated by recent studies of Candida albicans. The first generation of azole antifungals were imidazoles such as clotrimazole and miconazole. As with PDR1, TAC1 is evolutionarily divergent, and there are no unambiguous orthologs outside of the C. albicans-containing CTG clade. The first generation of research on antifungal resistance has focused on understanding the basis for acquired resistance in the experimentally tractable fungi Saccharomyces cerevisiae, C. albicans, and C. glabrata. The second generation of antifungal resistance research will explore the basis for intrinsic resistance in the diverse fungal pathogens that increasingly threaten immunocompromised patients, particularly Aspergillus, Fusarium, Scedosporium, and zygomycete species. Ultimately, understanding the molecular basis for intrinsic antifungal resistance will facilitate the design of second-generation inhibitors with an extended spectrum of activity.
The ergosterol biosynthesis pathway, in abbreviated form. Each arrow represents an enzymatic step. Genes encoding enzymes specifically targeted by antifungals are indicated. The pathway was deduced in S. cerevisiae (Lees et al., 1995) but appears to be valid for other fungi.
Alignment of Fks sequences encompassing the two hot spots for echinocandin resistance. Ca, C. albicans; Sc, S. cerevisiae; Fs, F. solani; Cn, C. neoformans; Ro, R. oryzae. Residues involved in acquired resistance are indicated (bold underline), as are positions predicted to play a role in intrinsic resistance (▲). All sequences represent Fks1, except R. oryzae Fks, which are arbitrarily numbered.
Alignment of partial Erg11/Cyp51 sequences from C. albicans (Ca), C. krusei (Ck), F. verticillioides (FvA, FvB), R. oryzae (RoA, RoB), and A. fumigatus (AfA, AfB). C. albicans Erg11 and A. fumigatus Cyp51A residues associated with acquired azole resistance are indicated (bold underline), with mutations listed above or below the wild-type sequence. Residues in the Ck, Fv, and Ro sequences that align with these mutations and are postulated to play a role in intrinsic azole resistance are also indicated (bold underline). Fv and Ro residue numbers are shown in parentheses since the true start sites were not identified.
Anatomy and evolution of the Pdr1 family of transcriptional regulators of azole and multidrug resistance. Sc, S. cerevisiae; Cg, C. glabrata. Bars indicate approximate locations of the DNA-binding, inhibitory, and activation domains. Underlined C. glabrata residues are conserved in either S. cerevisiae Pdr1 or Pdr3. Gain-of-function mutations are shown above or below the S. cerevisiae Pdr1 or Pdr3 sequences, respectively. Mutations associated with azole-resistance in C. glabrata Pdr1 are indicated (▲).