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

Three specific β(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 f...

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Veröffentlicht in:The Journal of biological chemistry 2011-02, Vol.286 (5), p.3484-3496
Hauptverfasser: Martins, Ivone M., Cortés, Juan C.G., Muñoz, Javier, Moreno, M. Belén, Ramos, Mariona, Clemente-Ramos, José A., Durán, Angel, Ribas, Juan C.
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container_end_page 3496
container_issue 5
container_start_page 3484
container_title The Journal of biological chemistry
container_volume 286
creator Martins, Ivone M.
Cortés, Juan C.G.
Muñoz, Javier
Moreno, M. Belén
Ramos, Mariona
Clemente-Ramos, José A.
Durán, Angel
Ribas, Juan C.
description Three specific β(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 (IC50 103–104-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 (IC50 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. Bgs4pbr1-8 contains the E700V change, four residues N-terminal from hot spot 1 defining a larger resistance hot spot 1-1 of 13 amino acids. Bgs4pbr1-6 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.
doi_str_mv 10.1074/jbc.M110.174300
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subjects Aminoglycosides - pharmacology
Antibiotics
Antifungal Agents - pharmacology
Antifungals
Candida
Caspofungin
Cell Wall
Drug Resistance, Fungal - genetics
Echinocandins - pharmacology
Enzyme Inhibitors
Enzyme Inhibitors - pharmacology
Fks Proteins
Glucan
Glucan Synthase
Glucosyltransferases - antagonists & inhibitors
Inhibitory Concentration 50
Membrane Enzymes
Microbiology
Mutation, Missense
Saccharomyces
Schizosaccharomyces - enzymology
Schizosaccharomyces pombe
Schizosaccharomyces pombe Proteins - antagonists & inhibitors
Terpenes - pharmacology
Yeast
title Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast
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