Chapter 44 : Molecular Detection of Antifungal Resistance

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Molecular Detection of Antifungal Resistance, Page 1 of 2

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The increasing need for clinically relevant antifungal susceptibility assays is driven by three recent developments in medical mycology: (i) the increasing incidence of fungal infection due to immunosuppression (associated with AIDS, organ and tissue transplantation, and aggressive treatments for cancer and autoimmune disease), (ii) the expanding number of antifungals with both shared and distinct mechanisms of action, and (iii) the recognition of wide variation in susceptibility due to both intrinsic and acquired antifungal resistance. With respect to disease-causing fungi, some of these conditions apply, but clearly in limited and specific ways. First, for most fungal pathogens and antifungals, the development of resistance during treatment is rare. Second, relatively few studies have directly examined the clinical relevance of antifungal susceptibility data. The majority of these mutations involve a single Cyp51A residue, G54, although at least four additional residues have also been implicated. The currently known mutations associated with azole resistance in Erg11 and Cyp51A are dispersed over 1.2 kbp of primary sequence. Echinocandins (caspofungin, micafungin, and anidulafungin) are the most recently introduced class of antifungals but are highly promising due to their mechanism-based selective toxicity. A great deal has been learned in recent years regarding molecular mechanisms of antifungal resistance, particularly in the yeasts and and the mold . In addition, simple and cost-effective approaches to measuring RNA expression and sequencing DNA are required.

Citation: Edlind T. 2011. Molecular Detection of Antifungal Resistance, p 677-684. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch44
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Image of FIGURE 1

Anatomy of transcriptional activator Pdr1, based on homology to Pdr1 and Pdr3. Gain-of-function mutations (indicated by vertical bars [ ; S. Katiyar and T. Edlind, unpublished data]) result in increased expression of MDR transporter genes whose products are responsible for azole efflux. Shaded areas indicate approximate locations of the DNA binding (DB), inhibitory, and activation domains. The total lengths range from 976 to 1,107 amino acids.

Citation: Edlind T. 2011. Molecular Detection of Antifungal Resistance, p 677-684. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch44
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Image of FIGURE 2

Alignment of Erg11 and Cyp51A sequences. Alignment was generated by ClustalW (vertical bars, identity; dots, conservative differences; hyphens, gaps introduced to optimize alignment). Residues mutated in azole-resistant clinical isolates ( ; for a review, see reference and references therein) are underlined, and the mutation is indicated above or below . Note that many of these mutations have not been experimentally confirmed to confer resistance.

Citation: Edlind T. 2011. Molecular Detection of Antifungal Resistance, p 677-684. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch44
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Image of FIGURE 3

Mutations conferring echinocandin resistance in and the indicated species localize to Fks1 or Fks2 hot spots 1 and 2. The mutated residue is underlined, with the observed change indicated below the residue. Dots indicate identity to the Fks1 residue. See text for references.

Citation: Edlind T. 2011. Molecular Detection of Antifungal Resistance, p 677-684. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch44
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