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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

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Abstract:

The most common agents of fungal infections include , , and , since these are ubiquitous and commensal fungal colonizers. This chapter focuses on the treatment of these three important fungal diseases, with an emphasis on . 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 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 B) 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 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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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
/content/10.1128/9781555815776.ch14.ch14fig01
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 and , including mutations and changes in gene expression (boxes outlined in gray).
10.1128/9781555815776/f0200-01_thmb.gif
10.1128/9781555815776/f0200-01.gif
Image of Figure 1.
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 and , including mutations and changes in gene expression (boxes outlined in gray).

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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Tables

Molecular Principles of Antifungal Drug Resistance
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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
/content/10.1128/9781555815776.ch14.ch14tab01
Table 1.
Transcription factors regulating resistance
Generic image for table
Table 1.

Transcription factors regulating resistance

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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