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Chapter 44 : Antifungal Drugs: The Current Armamentarium and Development of New Agents

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Abstract:

Disease and death caused by fungal infections have transitioned from a rare curiosity to a major global health problem. Because the vast majority of fungi capable of causing life-threatening infections target individuals with impaired immunity, recent decades have witnessed a stark rise in fungal infections due to medical interventions such as chemotherapy for cancer and immunosuppression for organ transplantation and due to the prevalence of HIV infection ( ). Pathogenic fungi are the causative agents of billions of infections annually, with ∼1.5 million attributable mortalities ( ). The public health burden is comparable to that observed with more notable infectious diseases such as tuberculosis and malaria, yet the impact of fungal infections on human health has been largely overlooked ( ).

Citation: Robbins N, Wright G, Cowen L. 2017. Antifungal Drugs: The Current Armamentarium and Development of New Agents, p 903-922. In Heitman J, Howlett B, Crous P, Stukenbrock E, James T, Gow N (ed), The Fungal Kingdom. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.FUNK-0002-2016
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Figures

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Figure 1

Structures and mechanisms of action of clinically relevant antifungal drugs. The azoles function by targeting the ergosterol biosynthetic enzyme lanosterol demethylase, encoded by ( and ) or and (), causing a block in the production of ergosterol and the accumulation of a toxic sterol produced by Erg3. This toxic sterol exerts a severe membrane stress on the cell. Polyenes such as amphotericin B primarily exist in the form of large extramembranous aggregates that extract ergosterol from lipid bilayers. Fungal cell walls are composed of (1,3)-β--glucans covalently linked to (1,6)-β--glucans as well as chitin, mannans, and cell wall proteins. The echinocandins act as noncompetitive inhibitors of (1,3)-β--glucan synthase (encoded by in , , and ) and thereby cause a loss of cell wall integrity and severe cell wall stress. Pyrimidines such as flucytosine become rapidly deaminated in the cytosol to generate 5-fluorouracil (5-FU) by fungal-specific cytosine deaminases. 5-FU acts as a potent antimetabolite that causes RNA miscoding and inhibits DNA synthesis. Adapted from reference with permission.

Citation: Robbins N, Wright G, Cowen L. 2017. Antifungal Drugs: The Current Armamentarium and Development of New Agents, p 903-922. In Heitman J, Howlett B, Crous P, Stukenbrock E, James T, Gow N (ed), The Fungal Kingdom. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.FUNK-0002-2016
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Image of Figure 2
Figure 2

Structures of compounds with antifungal activity. Chemical structures of antifungal molecules highlighted throughout the review. The description in brackets describes the molecular target of the chemical compound.

Citation: Robbins N, Wright G, Cowen L. 2017. Antifungal Drugs: The Current Armamentarium and Development of New Agents, p 903-922. In Heitman J, Howlett B, Crous P, Stukenbrock E, James T, Gow N (ed), The Fungal Kingdom. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.FUNK-0002-2016
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