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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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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Belén ; Ramos, Mariona ; Clemente-Ramos, José A. ; Durán, Angel ; Ribas, Juan C.</creator><creatorcontrib>Martins, Ivone M. ; Cortés, Juan C.G. ; Muñoz, Javier ; Moreno, M. Belén ; Ramos, Mariona ; Clemente-Ramos, José A. ; Durán, Angel ; Ribas, Juan C.</creatorcontrib><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.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M110.174300</identifier><identifier>PMID: 21115488</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>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</subject><ispartof>The Journal of biological chemistry, 2011-02, Vol.286 (5), p.3484-3496</ispartof><rights>2011 © 2011 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2011 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-671b74c7428ac29ff507b025678bd9ac8ef5b844393c18166089846706cb734c3</citedby><cites>FETCH-LOGICAL-c498t-671b74c7428ac29ff507b025678bd9ac8ef5b844393c18166089846706cb734c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030354/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030354/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21115488$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martins, Ivone M.</creatorcontrib><creatorcontrib>Cortés, Juan C.G.</creatorcontrib><creatorcontrib>Muñoz, Javier</creatorcontrib><creatorcontrib>Moreno, M. Belén</creatorcontrib><creatorcontrib>Ramos, Mariona</creatorcontrib><creatorcontrib>Clemente-Ramos, José A.</creatorcontrib><creatorcontrib>Durán, Angel</creatorcontrib><creatorcontrib>Ribas, Juan C.</creatorcontrib><title>Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><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. 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Belén</creator><creator>Ramos, Mariona</creator><creator>Clemente-Ramos, José A.</creator><creator>Durán, Angel</creator><creator>Ribas, Juan C.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>M7N</scope><scope>5PM</scope></search><sort><creationdate>20110204</creationdate><title>Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast</title><author>Martins, Ivone M. ; Cortés, Juan C.G. ; Muñoz, Javier ; Moreno, M. 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Belén</creatorcontrib><creatorcontrib>Ramos, Mariona</creatorcontrib><creatorcontrib>Clemente-Ramos, José A.</creatorcontrib><creatorcontrib>Durán, Angel</creatorcontrib><creatorcontrib>Ribas, Juan C.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Martins, Ivone M.</au><au>Cortés, Juan C.G.</au><au>Muñoz, Javier</au><au>Moreno, M. Belén</au><au>Ramos, Mariona</au><au>Clemente-Ramos, José A.</au><au>Durán, Angel</au><au>Ribas, Juan C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2011-02-04</date><risdate>2011</risdate><volume>286</volume><issue>5</issue><spage>3484</spage><epage>3496</epage><pages>3484-3496</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21115488</pmid><doi>10.1074/jbc.M110.174300</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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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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