Molecular Principles of Antifungal Drug Resistance

Dominique Sanglard; Theodore C. White

doi:10.1128/9781555815776.ch14

Chapter 14 : Molecular Principles of Antifungal Drug Resistance

Authors: Dominique Sanglard¹, Theodore C. White²

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Affiliations: 1: Institute of Microbiology, University Hospital Lausanne, Rue de Bugnon 44, CH-1011 Lausanne, Switzerland; 2: Department of Pathobiology, School of Public Health and Community Medicine, University of Washington and Seattle Biomedical Research Institute, 307 Westlake Ave., N., Suite 500, Seattle, WA 98109-5219

Content Type: Monograph

Publication Year: 2006

Category: Fungi and Fungal Pathogenesis

Book DOI: 10.1128/9781555815776

Chapter DOI: 10.1128/9781555815776.ch14

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Abstract:

The most common agents of fungal infections include Candida, Cryptococcus, and Aspergillus, since these are ubiquitous and commensal fungal colonizers. This chapter focuses on the treatment of these three important fungal diseases, with an emphasis on Candida. However, the effectiveness of these therapies against other fungal infections also needs to be considered. Currently available antifungal drugs can be grouped into four main categories-polyenes, nucleic acid synthesis inhibitors, ergosterol biosynthesis inhibitors (EBI), and echinocandins. The polyenes are a class of compounds with an amphipathic nature. The echinocandin caspofungin has only recently become clinically available, and so the number of strains with caspofungin resistance, with or without cross-resistance to other echinocandins, is limited. The chapter summarizes the current knowledge about the regulation of resistance in C. albicans sand in other yeast species. In addition to the antifungal drug resistance function of CaMDR1, the other genes have oxidoreductive functions (GRP2 and IFD5) or are potentially involved in pyridoxine (vitamin B6) synthesis (IPF5987 and SNZ1). One of the most important host factors in treating a fungal infection is the patient’s compliance with the drug regimen. Resistance to antifungal drugs has been observed with the azoles and with 5FC. The molecular mechanisms of resistance of C. albicans to azole drugs, including alterations in the target enzyme and in drug efflux pumps, have been well defined.

Citation: Sanglard D, White T. 2006. Molecular Principles of Antifungal Drug Resistance, p 197-212. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch14

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Molecular Principles of Antifungal Drug Resistance

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Figure 1.

Azole interactions with fungal cells. Azole antifungals interact with a fungal cell in several ways. First, azole drugs enter the cell. There are conflicting data concerning the mechanisms of import. The azoles then inhibit the azole target enzyme Erg11. Inhibition of that enzyme alters sterol synthesis, which alters membrane sterols, replacing ergo-sterol with 14-α methyl sterols. Azoles are removed from the cell by two types of efflux pump, the ABC transporters, including Cdr1 and Cdr2, and the major facilitators, including Mdr1 and potentially Flu1. Mechanisms of resistance include alterations in ERG11, CDR1, CDR2, and MDR1, including mutations and changes in gene expression (boxes outlined in gray).

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Figure 1.

References

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Tables

Molecular Principles of Antifungal Drug Resistance

/content/10.1128/9781555815776.ch14.ch14tab01

Table 1.

Transcription factors regulating resistance

Table 1.

Transcription factors regulating resistance