Role for Fks1 in the Intrinsic Echinocandin Resistance of
            <i>Fusarium solani</i>
            as Evidenced by Hybrid Expression in
            <i>Saccharomyces cerevisiae</i>

Katiyar, Säntosh K.; Edlind, Thomas D.

doi:10.1128/aac.00020-09

Cited by 63 publications

(62 citation statements)

References 44 publications

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“…The finding of this variability in the resistance to echinocandins was possible because the mutants were selected for their resistance to papulacandin (25). Most of the mutants described have been isolated as resistant to echinocandins (12,21,22,(37)(38)(39)(40)(41)(42)(43). We have inserted some of these mutations into bgs4 ϩ , and none of them altered the in vivo sensitivity of the cells to papulacandin and enfumafungin but produced variable degrees of resistance to echinocandins, 7 showing that each antifungal family acts through different sites of the GS enzyme and that some resistances may be specific to a given antifungal family.…”

Section: Discussionmentioning

confidence: 99%

“…Fungal resistance to GS inhibitors is clearly associated with mutations in conserved short regions (hot spots) of the Fks proteins, indicating that this mechanism is well conserved in fungi (12,19,20). In addition, intrinsic echinocandin-resistant fungi contain natural substitutions in the conserved Fks region that are determinants of their resistance (19,(21)(22)(23). Most of the mutants resistant to GS inhibitors have been isolated as resistant to echinocandins.…”

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confidence: 99%

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Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast

Martins¹,

Cortés²,

Muñoz³

et al. 2011

Journal of Biological Chemistry

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Three specific ␤(1,3)glucan synthase (GS) inhibitor families, papulacandins, acidic terpenoids, and echinocandins, have been analyzed in Schizosaccharomyces pombe wild-type and papulacandin-resistant cells and GS activities. Papulacandin and enfumafungin produced similar in vivo effects, different from that of echinocandins. Also, papulacandin was the strongest in vitro GS inhibitor (IC 50 10 3 -10 4 -fold lower than with enfumafungin or pneumocandin), but caspofungin was by far the most efficient antifungal because of the following. 1) It was the only drug that affected resistant cells (minimal inhibitory concentration close to that of the wild type). 2) It was a strong inhibitor of wild-type GS (IC 50 close to that of papulacandin). 3) It was the best inhibitor of mutant GS. Moreover, caspofungin showed a special effect for two GS inhibition activities, of high and low affinity, separated by 2 log orders, with no increase in inhibition. pbr1-8 and pbr1-6 resistances are due to single substitutions in the essential Bgs4 GS, located close to the resistance hot spot 1 region described in Saccharomyces and Candida Fks mutants. Bgs4 pbr1-8 contains the E700V change, four residues N-terminal from hot spot 1 defining a larger resistance hot spot 1-1 of 13 amino acids. Bgs4 pbr1-6 contains the W760S substitution, defining a new resistance hot spot 1-2. We observed spontaneous revertants of the spherical pbr1-6 phenotype and found that an additional A914V change is involved in the recovery of the wild-type cell shape, but it maintains the resistance phenotype. A better understanding of the mechanism of action of the antifungals available should help to improve their activity and to identify new antifungal targets.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast

Martins¹,

Cortés²,

Muñoz³

et al. 2011

Journal of Biological Chemistry

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“…Transformants were selected on SD-ura. To confirm desired plasmid recombination, yeast lysates (19) were screened by PCR with Taq polymerase (New England BioLabs) and vector primer pJK90F or pJK90R (see Table S1 in the supplemental material) in conjunction with various FKS1 coding region primers (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Topological and Mutational Analysis of Saccharomyces cerevisiae Fks1

Johnson

Edlind

2012

Eukaryot Cell

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ABSTRACTFks1, with orthologs in nearly all fungi as well as plants and many protists, plays a central role in fungal cell wall formation as the putative catalytic component of β-1,3-glucan synthase. It is also the target for an important new antifungal group, the echinocandins, as evidenced by the localization of resistance-conferring mutations to Fks1 hot spots 1, 2, and 3 (residues 635 to 649, 1354 to 1361, and 690 to 700, respectively). Since Fks1 is an integral membrane protein and echinocandins are cyclic peptides with lipid tails, Fks1 topology is key to understanding its function and interaction with echinocandins. We used hemagglutinin (HA)-Suc2-His4C fusions to C-terminally truncatedSaccharomyces cerevisiaeFks1 to experimentally define its topology and site-directed mutagenesis to test function of selected residues. Of the 15 to 18 transmembrane helices predictedin silicofor Fks1 from evolutionarily diverse fungi, 13 were experimentally confirmed. The N terminus (residues 1 to 445) is cytosolic and the C terminus (residues 1823 to 1876) external; both are essential to Fks1 function. The cytosolic central domain (residues 715 to 1294) includes newly recognized homology to glycosyltransferases, and residues potentially involved in substrate UDP-glucose binding and catalysis are essential. All three hot spots are external, with hot spot 1 adjacent to and hot spot 3 largely embedded within the outer leaflet of the membrane. This topology suggests a model in which echinocandins interact through their lipid tails with hot spot 3 and through their cyclic peptides with hot spots 1 and 2.

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“…Several mutations have been linked to reduced susceptibility to echinocandins in Candida spp. (9,10) and in the filamentous fungi Fusarium solani, Scedosporium prolificans, and A. fumigatus (11,12). Also, the echinocandins increase the efficiency of phagocyte killing, as the inhibition of ␤-glucan synthase results in a pathogen that is more recognizable to host cells (13).…”

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confidence: 99%

Modulation of Alternaria infectoria Cell Wall Chitin and Glucan Synthesis by Cell Wall Synthase Inhibitors

Fernandes

Anjos

Walker

et al. 2014

Antimicrob Agents Chemother

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cThe present work reports the effects of caspofungin, a ␤-1,3-glucan synthase inhibitor, and nikkomycin Z, an inhibitor of chitin synthases, on two strains of Alternaria infectoria, a melanized fungus involved in opportunistic human infections and respiratory allergies. One of the strains tested, IMF006, bore phenotypic traits that conferred advantages in resisting antifungal treatment. First, the resting cell wall chitin content was higher and in response to caspofungin, the chitin level remained constant. In the other strain, IMF001, the chitin content increased upon caspofungin treatment to values similar to basal IMF006 levels. Moreover, upon caspofungin treatment, the FKS1 gene was upregulated in IMF006 and downregulated in IMF001. In addition, the resting ␤-glucan content was also different in both strains, with higher levels in IMF001 than in IMF006. However, this did not provide any advantage with respect to echinocandin resistance. We identified eight different chitin synthase genes and studied relative gene expression when the fungus was exposed to the antifungals under study. In both strains, exposure to caspofungin and nikkomycin Z led to modulation of the expression of class V and VII chitin synthase genes, suggesting its importance in the robustness of A. infectoria. The pattern of A. infectoria phagocytosis and activation of murine macrophages by spores was not affected by caspofungin. Monotherapy with nikkomycin Z and caspofungin provided only fungistatic inhibition, while a combination of both led to fungal cell lysis, revealing a strong synergistic action between the chitin synthase inhibitor and the ␤-glucan synthase inhibitor against this fungus.

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Role for Fks1 in the Intrinsic Echinocandin Resistance of Fusarium solani as Evidenced by Hybrid Expression in Saccharomyces cerevisiae

Cited by 63 publications

References 44 publications

Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast

Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast

Topological and Mutational Analysis of Saccharomyces cerevisiae Fks1

Modulation of Alternaria infectoria Cell Wall Chitin and Glucan Synthesis by Cell Wall Synthase Inhibitors

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