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Review
. 2008 May;7(5):747-64.
doi: 10.1128/EC.00041-08. Epub 2008 Mar 28.

Stress, drugs, and evolution: the role of cellular signaling in fungal drug resistance

Leah E Cowen  1 , William J Steinbach
Affiliations
Review

Stress, drugs, and evolution: the role of cellular signaling in fungal drug resistance

Leah E Cowen et al. Eukaryot Cell. 2008 May.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Select antifungal drugs and their targets. (A) Triazoles inhibit the fungal cytochrome P45014DM (also known as lanosterol 14α-demethylase; encoded by ERG11 in C. albicans and C. neoformans and by cyp51A and cyp51B in A. fumigatus), thereby blocking the production of ergosterol, the main sterol in the fungal cell membrane, causing the accumulation of a toxic sterol intermediate and resulting in cell membrane stress. Ergosterol biosynthesis occurs in the endoplasmic reticulum. (B) Polyenes bind to ergosterol in the fungal cell membrane, forming membrane-spanning channels that cause leakage of cellular components and osmotic cellular lysis. (C) Flucytosine is deaminated into 5-fluorouracil and, subsequently, 5-fluorodeoxyuridine monophosphate, which inhibits thymidylate synthase and interferes with DNA synthesis; 5-fluorouracil is also converted into 5-fluorouridine triphosphate, which disrupts RNA synthesis. (D) Echinocandins inhibit (1,3)-β-d-glucan synthase (the catalytic subunit is encoded by FKS1 in C. albicans, C. neoformans, and A. fumigatus and by FKS1 and FKS2 in S. cerevisiae; RHO1 encodes a positive regulator of glucan synthase activity), resulting in cell wall stress and a loss of cell wall integrity. +, present; −, absent. (Adapted from reference with permission of the publisher.)
FIG. 2.
FIG. 2.
C. albicans triazole resistance mechanisms. (A) Mutation or upregulation of the target of the triazoles, cytochrome P45014DM (also known as lanosterol 14α-demethylase; encoded by ERG11 in C. albicans), confers resistance to triazoles by minimizing the impact of the drug on the target. (B) Constitutive upregulation of members of the ABC transporter family of multidrug efflux pumps confers resistance to multiple triazoles, and upregulation of a major facilitator transporter confers resistance to fluconazole by minimizing the impact of the drug on the cell. (C) Loss-of-function mutation of Erg3 confers triazole resistance by blocking the accumulation of the toxic sterol intermediate that would otherwise accumulate when cytochrome P45014DM is inhibited by the triazoles. (D) The molecular chaperone Hsp90 stabilizes calcineurin, thereby enabling calcineurin-dependent stress responses that are required for triazole tolerance of wild-type strains and resistance of many mutants, including those with loss of function of Erg3. Multiple downstream effectors of calcineurin mediate cellular responses to azoles, including the transcription factor Crz1. (Adapted from reference with permission of the publisher.)
FIG. 3.
FIG. 3.
C. albicans echinocandin resistance mechanisms. (A) Mutation of (1, 3)-β-d-glucan synthase, the target of the echinocandins encoded by FKS1, confers resistance to echinocandins by minimizing the impact of the drug on the cell. (B) Rho1 is a positive regulator of glucan synthase, and it contributes to tolerance of the echinocandins by mediating stress responses, including activation of the PKC cell wall integrity pathway and upregulation of synthesis of other cell wall components, such as chitin. (Adapted from reference with permission of the publisher.)
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References

    1. Abruzzo, G. K., A. M. Flattery, C. J. Gill, L. Kong, J. G. Smith, V. B. Pikounis, J. M. Balkovec, A. F. Bouffard, J. F. Dropinski, H. Rosen, H. Kropp, and K. Bartizal. 1997. Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis. Antimicrob. Agents Chemother. 412333-2338. - PMC - PubMed
    1. Aller, A. I., R. Claro, C. Castro, C. Serrano, M. F. Colom, and E. Martin-Mazuelos. 2007. Antifungal susceptibility of Cryptococcus neoformans isolates in HIV-infected patients to fluconazole, itraconazole and voriconazole in Spain: 1994-1996 and 1997-2005. Chemotherapy 53300-305. - PubMed
    1. Anderson, J. B. 2005. Evolution of antifungal-drug resistance: mechanisms and pathogen fitness. Nat. Rev. Microbiol. 3547-556. - PubMed
    1. Araujo, R., C. Pina-Vaz, and A. Goncalves Rodrigues. 2007. Susceptibility of environmental versus clinical strains of pathogenic Aspergillus. Int. J. Antimicrob. Agents 29108-111. - PubMed
    1. Armengou, A., C. Porcar, J. Mascaro, and F. Garcia-Bragado. 1996. Possible development of resistance to fluconazole during suppressive therapy for AIDS-associated cryptococcal meningitis. Clin. Infect. Dis. 231337-1338. - PubMed

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