Capreomycin Binds across the Ribosomal Subunit Interface Using tlyA-Encoded 2′-O-Methylations in 16S and 23S rRNAs
The cyclic peptide antibiotics capreomycin and viomycin are generally effective against the bacterial pathogen Mycobacterium tuberculosis. However, recent virulent isolates have become resistant by inactivation of their tlyA gene. We show here that tlyA encodes a 2′-O-methyltransferase that modifies...
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| Veröffentlicht in: | Molecular cell 2006-07, Vol.23 (2), p.173-182 |
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| creator | Johansen, Shanna K. Maus, Courtney E. Plikaytis, Bonnie B. Douthwaite, Stephen |
| description | The cyclic peptide antibiotics capreomycin and viomycin are generally effective against the bacterial pathogen
Mycobacterium tuberculosis. However, recent virulent isolates have become resistant by inactivation of their
tlyA gene. We show here that
tlyA encodes a 2′-O-methyltransferase that modifies nucleotide C1409 in helix 44 of 16S rRNA and nucleotide C1920 in helix 69 of 23S rRNA. Loss of these previously unidentified rRNA methylations confers resistance to capreomycin and viomycin. Many bacterial genera including enterobacteria lack a
tlyA gene and the ensuing methylations and are less susceptible than mycobacteria to capreomycin and viomycin. We show that expression of recombinant
tlyA in
Escherichia coli markedly increases susceptibility to these drugs. When the ribosomal subunits associate during translation, the two
tlyA-encoded methylations are brought into close proximity at interbridge B2a. The location of these methylations indicates the binding site and inhibitory mechanism of capreomycin and viomycin at the ribosome subunit interface. |
| doi_str_mv | 10.1016/j.molcel.2006.05.044 |
| format | Article |
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Mycobacterium tuberculosis. However, recent virulent isolates have become resistant by inactivation of their
tlyA gene. We show here that
tlyA encodes a 2′-O-methyltransferase that modifies nucleotide C1409 in helix 44 of 16S rRNA and nucleotide C1920 in helix 69 of 23S rRNA. Loss of these previously unidentified rRNA methylations confers resistance to capreomycin and viomycin. Many bacterial genera including enterobacteria lack a
tlyA gene and the ensuing methylations and are less susceptible than mycobacteria to capreomycin and viomycin. We show that expression of recombinant
tlyA in
Escherichia coli markedly increases susceptibility to these drugs. When the ribosomal subunits associate during translation, the two
tlyA-encoded methylations are brought into close proximity at interbridge B2a. The location of these methylations indicates the binding site and inhibitory mechanism of capreomycin and viomycin at the ribosome subunit interface.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2006.05.044</identifier><identifier>PMID: 16857584</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antibiotics, Antitubercular - pharmacology ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Base Sequence ; Capreomycin - pharmacology ; Cloning, Molecular ; Drug Resistance, Bacterial - genetics ; Escherichia coli ; Escherichia coli - drug effects ; Escherichia coli - genetics ; Escherichia coli - metabolism ; Mass Spectrometry ; Methylation ; MICROBIO ; Molecular Sequence Data ; Mutation ; Mycobacteriaceae - drug effects ; Mycobacterium tuberculosis ; Nucleic Acid Conformation ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; Ribosomes - genetics ; Ribosomes - metabolism ; RNA ; RNA, Bacterial - drug effects ; RNA, Bacterial - genetics ; RNA, Bacterial - metabolism ; RNA, Ribosomal, 16S - genetics ; RNA, Ribosomal, 16S - metabolism ; RNA, Ribosomal, 28S - genetics ; RNA, Ribosomal, 28S - metabolism</subject><ispartof>Molecular cell, 2006-07, Vol.23 (2), p.173-182</ispartof><rights>2006 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c437t-2c91494b00c2a7c69619347f653176a4584302b8993197771e5a36432bbed18d3</citedby><cites>FETCH-LOGICAL-c437t-2c91494b00c2a7c69619347f653176a4584302b8993197771e5a36432bbed18d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1097276506004333$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16857584$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Johansen, Shanna K.</creatorcontrib><creatorcontrib>Maus, Courtney E.</creatorcontrib><creatorcontrib>Plikaytis, Bonnie B.</creatorcontrib><creatorcontrib>Douthwaite, Stephen</creatorcontrib><title>Capreomycin Binds across the Ribosomal Subunit Interface Using tlyA-Encoded 2′-O-Methylations in 16S and 23S rRNAs</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>The cyclic peptide antibiotics capreomycin and viomycin are generally effective against the bacterial pathogen
Mycobacterium tuberculosis. However, recent virulent isolates have become resistant by inactivation of their
tlyA gene. We show here that
tlyA encodes a 2′-O-methyltransferase that modifies nucleotide C1409 in helix 44 of 16S rRNA and nucleotide C1920 in helix 69 of 23S rRNA. Loss of these previously unidentified rRNA methylations confers resistance to capreomycin and viomycin. Many bacterial genera including enterobacteria lack a
tlyA gene and the ensuing methylations and are less susceptible than mycobacteria to capreomycin and viomycin. We show that expression of recombinant
tlyA in
Escherichia coli markedly increases susceptibility to these drugs. When the ribosomal subunits associate during translation, the two
tlyA-encoded methylations are brought into close proximity at interbridge B2a. The location of these methylations indicates the binding site and inhibitory mechanism of capreomycin and viomycin at the ribosome subunit interface.</description><subject>Antibiotics, Antitubercular - pharmacology</subject><subject>Bacterial Proteins - genetics</subject><subject>Bacterial Proteins - metabolism</subject><subject>Base Sequence</subject><subject>Capreomycin - pharmacology</subject><subject>Cloning, Molecular</subject><subject>Drug Resistance, Bacterial - genetics</subject><subject>Escherichia coli</subject><subject>Escherichia coli - drug effects</subject><subject>Escherichia coli - genetics</subject><subject>Escherichia coli - metabolism</subject><subject>Mass Spectrometry</subject><subject>Methylation</subject><subject>MICROBIO</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Mycobacteriaceae - drug effects</subject><subject>Mycobacterium tuberculosis</subject><subject>Nucleic Acid Conformation</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>Ribosomes - genetics</subject><subject>Ribosomes - metabolism</subject><subject>RNA</subject><subject>RNA, Bacterial - drug effects</subject><subject>RNA, Bacterial - genetics</subject><subject>RNA, Bacterial - metabolism</subject><subject>RNA, Ribosomal, 16S - genetics</subject><subject>RNA, Ribosomal, 16S - metabolism</subject><subject>RNA, Ribosomal, 28S - genetics</subject><subject>RNA, Ribosomal, 28S - metabolism</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctu1DAUhiNERS_wBgh5xS7Bjm_xBmkYFVqppVKHri3HOUM9SuzBdpBmxzPxSDxJPcxI7OjKlvyd3zr_V1VvCW4IJuLDppnCaGFsWoxFg3mDGXtRnRGsZM2IYC-P91YKflqdp7TBmDDeqVfVKREdl7xjZ1Vemm2EMO2s8-iT80NCxsaQEsqPgO5dH1KYzIhWcz97l9G1zxDXxgJ6SM5_R3ncLepLb8MAA2r__Ppd39W3kB93o8ku-IRKLBErZHx5pisU778u0uvqZG3GBG-O50X18Pny2_Kqvrn7cr1c3NSWUZnr1irCFOsxtq2RVihBFGVyLTglUpiyC6O47TulKFFSSgLcUMFo2_cwkG6gF9X7Q-42hh8zpKwnl0plo_EQ5qRFJ_YZ_FmQyJbhjpACsgP4t6MIa72NbjJxpwnWey16ow9a9F6LxlwXLWXs3TF_7icY_g0dPRTg4wGAUsdPB1En68BbGFwEm_UQ3P9_eALTZ56M</recordid><startdate>20060721</startdate><enddate>20060721</enddate><creator>Johansen, Shanna K.</creator><creator>Maus, Courtney E.</creator><creator>Plikaytis, Bonnie B.</creator><creator>Douthwaite, Stephen</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7QL</scope><scope>7TM</scope><scope>C1K</scope><scope>7X8</scope></search><sort><creationdate>20060721</creationdate><title>Capreomycin Binds across the Ribosomal Subunit Interface Using tlyA-Encoded 2′-O-Methylations in 16S and 23S rRNAs</title><author>Johansen, Shanna K. ; Maus, Courtney E. ; Plikaytis, Bonnie B. ; Douthwaite, Stephen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c437t-2c91494b00c2a7c69619347f653176a4584302b8993197771e5a36432bbed18d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Antibiotics, Antitubercular - pharmacology</topic><topic>Bacterial Proteins - genetics</topic><topic>Bacterial Proteins - metabolism</topic><topic>Base Sequence</topic><topic>Capreomycin - pharmacology</topic><topic>Cloning, Molecular</topic><topic>Drug Resistance, Bacterial - genetics</topic><topic>Escherichia coli</topic><topic>Escherichia coli - drug effects</topic><topic>Escherichia coli - genetics</topic><topic>Escherichia coli - metabolism</topic><topic>Mass Spectrometry</topic><topic>Methylation</topic><topic>MICROBIO</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Mycobacteriaceae - drug effects</topic><topic>Mycobacterium tuberculosis</topic><topic>Nucleic Acid Conformation</topic><topic>Recombinant Proteins - genetics</topic><topic>Recombinant Proteins - metabolism</topic><topic>Ribosomes - genetics</topic><topic>Ribosomes - metabolism</topic><topic>RNA</topic><topic>RNA, Bacterial - drug effects</topic><topic>RNA, Bacterial - genetics</topic><topic>RNA, Bacterial - metabolism</topic><topic>RNA, Ribosomal, 16S - genetics</topic><topic>RNA, Ribosomal, 16S - metabolism</topic><topic>RNA, Ribosomal, 28S - genetics</topic><topic>RNA, Ribosomal, 28S - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Johansen, Shanna K.</creatorcontrib><creatorcontrib>Maus, Courtney E.</creatorcontrib><creatorcontrib>Plikaytis, Bonnie B.</creatorcontrib><creatorcontrib>Douthwaite, Stephen</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nucleic Acids Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Johansen, Shanna K.</au><au>Maus, Courtney E.</au><au>Plikaytis, Bonnie B.</au><au>Douthwaite, Stephen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Capreomycin Binds across the Ribosomal Subunit Interface Using tlyA-Encoded 2′-O-Methylations in 16S and 23S rRNAs</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2006-07-21</date><risdate>2006</risdate><volume>23</volume><issue>2</issue><spage>173</spage><epage>182</epage><pages>173-182</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>The cyclic peptide antibiotics capreomycin and viomycin are generally effective against the bacterial pathogen
Mycobacterium tuberculosis. However, recent virulent isolates have become resistant by inactivation of their
tlyA gene. We show here that
tlyA encodes a 2′-O-methyltransferase that modifies nucleotide C1409 in helix 44 of 16S rRNA and nucleotide C1920 in helix 69 of 23S rRNA. Loss of these previously unidentified rRNA methylations confers resistance to capreomycin and viomycin. Many bacterial genera including enterobacteria lack a
tlyA gene and the ensuing methylations and are less susceptible than mycobacteria to capreomycin and viomycin. We show that expression of recombinant
tlyA in
Escherichia coli markedly increases susceptibility to these drugs. When the ribosomal subunits associate during translation, the two
tlyA-encoded methylations are brought into close proximity at interbridge B2a. The location of these methylations indicates the binding site and inhibitory mechanism of capreomycin and viomycin at the ribosome subunit interface.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>16857584</pmid><doi>10.1016/j.molcel.2006.05.044</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Free Full-Text Journals in Chemistry |
| subjects | Antibiotics, Antitubercular - pharmacology Bacterial Proteins - genetics Bacterial Proteins - metabolism Base Sequence Capreomycin - pharmacology Cloning, Molecular Drug Resistance, Bacterial - genetics Escherichia coli Escherichia coli - drug effects Escherichia coli - genetics Escherichia coli - metabolism Mass Spectrometry Methylation MICROBIO Molecular Sequence Data Mutation Mycobacteriaceae - drug effects Mycobacterium tuberculosis Nucleic Acid Conformation Recombinant Proteins - genetics Recombinant Proteins - metabolism Ribosomes - genetics Ribosomes - metabolism RNA RNA, Bacterial - drug effects RNA, Bacterial - genetics RNA, Bacterial - metabolism RNA, Ribosomal, 16S - genetics RNA, Ribosomal, 16S - metabolism RNA, Ribosomal, 28S - genetics RNA, Ribosomal, 28S - metabolism |
| title | Capreomycin Binds across the Ribosomal Subunit Interface Using tlyA-Encoded 2′-O-Methylations in 16S and 23S rRNAs |
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