Resistance to echinocandin-class antifungal drugs

被引:381
作者
Perlin, David S. [1 ]
机构
[1] UMDNJ, New Jersey Med Sch, Publ Hlth Res Inst, Newark, NJ USA
关键词
echinocandin; glucan synthase; Fks1; caspofungin; anidulafungin; micafungin;
D O I
10.1016/j.drup.2007.04.002
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandin drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking beta-1,3-D-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two "hot-spot" regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by 1000-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom. (c) 2007 Elsevier Ltd. All rights reserved.
引用
收藏
页码:121 / 130
页数:10
相关论文
共 82 条
[11]   Understanding the microbiology of the Aspergillus cell wall and the efficacy of caspofungin [J].
Douglas, Cameron M. .
MEDICAL MYCOLOGY, 2006, 44 :S95-S99
[12]   Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors [J].
Douglas, CM ;
DIppolito, JA ;
Shei, GJ ;
Meinz, M ;
Onishi, J ;
Marrinan, JA ;
Li, W ;
Abruzzo, GK ;
Flattery, A ;
Bartizal, K ;
Mitchell, A ;
Kurtz, MB .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1997, 41 (11) :2471-2479
[13]   A SACCHAROMYCES-CEREVISIAE MUTANT WITH ECHINOCANDIN-RESISTANT 1,3-BETA-D-GLUCAN SYNTHASE [J].
DOUGLAS, CM ;
MARRINAN, JA ;
LI, W ;
KURTZ, MB .
JOURNAL OF BACTERIOLOGY, 1994, 176 (18) :5686-5696
[14]  
Douglas CM, 2001, MED MYCOL, V39, P55, DOI 10.1080/mmy.39.1.55.66
[15]   THE SACCHAROMYCES-CEREVISIAE FKS1 (ETG1) GENE ENCODES AN INTEGRAL MEMBRANE-PROTEIN WHICH IS A SUBUNIT OF 1,3-BETA-D-GLUCAN SYNTHASE [J].
DOUGLAS, CM ;
FOOR, F ;
MARRINAN, JA ;
MORIN, N ;
NIELSEN, JB ;
DAHL, AM ;
MAZUR, P ;
BAGINSKY, W ;
LI, WL ;
ELSHERBEINI, M ;
CLEMAS, JA ;
MANDALA, SM ;
FROMMER, BR ;
KURTZ, MB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (26) :12907-12911
[16]   The echinocandin "target" identified by cross-linking is a homolog of Pil1 and Lsp1, sphingolipid-dependent regulators of cell wall integrity signaling [J].
Edlind, TD ;
Katiyar, SK .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2004, 48 (11) :4491-4491
[17]   DYNAMICS AND ORGANIZATION OF MAP KINASE SIGNAL PATHWAYS [J].
ERREDE, B ;
CADE, RM ;
YASHAR, BM ;
KAMADA, Y ;
LEVIN, DE ;
IRIE, K ;
MATSUMOTO, K .
MOLECULAR REPRODUCTION AND DEVELOPMENT, 1995, 42 (04) :477-485
[18]  
Espinel-Ingroff Ana, 2003, Revista Iberoamericana de Micologia, V20, P121
[19]   Characterization of Aspergillus fumigatus mutants with reduced susceptibility to caspofungin [J].
Gardiner, RE ;
Souteropoulos, P ;
Park, S ;
Perlin, DS .
MEDICAL MYCOLOGY, 2005, 43 :S299-S305
[20]   Regulation of the Saccharomyces cerevisiae Slt2 kinase pathway by the stress-inducible Sdp1 dual specificity phosphatase [J].
Hahn, JS ;
Thiele, DJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (24) :21278-21284