Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis
Isoniazid (INH) is a key agent in the treatment of tuberculosis. In Mycobacterium tuberculosis, INH is converted to its active form by KatG, a catalase-peroxidase, and attacks InhA, which is essential for the synthesis of mycolic acids. We sequenced furA-katG and fabG1-inhA in 108 INH-resistant (INH...
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| Veröffentlicht in: | Molecular microbiology 2011-03, Vol.79 (6), p.1615-1628 |
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| creator | Ando, Hiroki Kitao, Tomoe Miyoshi-Akiyama, Tohru Kato, Seiya Mori, Toru Kirikae, Teruo |
| description | Isoniazid (INH) is a key agent in the treatment of tuberculosis. In Mycobacterium tuberculosis, INH is converted to its active form by KatG, a catalase-peroxidase, and attacks InhA, which is essential for the synthesis of mycolic acids. We sequenced furA-katG and fabG1-inhA in 108 INH-resistant (INHr) and 51 INH-susceptible (INHs) isolates, and found three mutations in the furA-katG intergenic region (Intg-⁷a, Inta-¹⁰c and Intg-¹²a) in four of 108 INHr isolates (4%), and the furAc⁴¹t mutation with an amino acid substitution in 18 INHr isolates (17%). These mutations were not found in any of 51 INHs isolates tested. We reconstructed these mutations in isogenic strains to determine whether they conferred INH resistance. We found that the Intg-⁷a, Inta-¹⁰c and Intg-¹²a single mutations in the furA-katG intergenic region decreased katG expression and conferred INH resistance. In contrast, the furAc⁴¹t mutation was not sufficient to confer INH resistance. These results suggested that downregulation of katG is a mechanism of INH resistance in M. tuberculosis and that mutations in the furA-katG intergenic region play a role in this resistance mechanism. |
| doi_str_mv | 10.1111/j.1365-2958.2011.07547.x |
| format | Article |
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In Mycobacterium tuberculosis, INH is converted to its active form by KatG, a catalase-peroxidase, and attacks InhA, which is essential for the synthesis of mycolic acids. We sequenced furA-katG and fabG1-inhA in 108 INH-resistant (INHr) and 51 INH-susceptible (INHs) isolates, and found three mutations in the furA-katG intergenic region (Intg-⁷a, Inta-¹⁰c and Intg-¹²a) in four of 108 INHr isolates (4%), and the furAc⁴¹t mutation with an amino acid substitution in 18 INHr isolates (17%). These mutations were not found in any of 51 INHs isolates tested. We reconstructed these mutations in isogenic strains to determine whether they conferred INH resistance. We found that the Intg-⁷a, Inta-¹⁰c and Intg-¹²a single mutations in the furA-katG intergenic region decreased katG expression and conferred INH resistance. In contrast, the furAc⁴¹t mutation was not sufficient to confer INH resistance. These results suggested that downregulation of katG is a mechanism of INH resistance in M. tuberculosis and that mutations in the furA-katG intergenic region play a role in this resistance mechanism.</description><identifier>ISSN: 0950-382X</identifier><identifier>EISSN: 1365-2958</identifier><identifier>DOI: 10.1111/j.1365-2958.2011.07547.x</identifier><identifier>PMID: 21244531</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Amino acids ; Antitubercular Agents - pharmacology ; Bacteria ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Bacteriology ; Biological and medical sciences ; Catalase - genetics ; Catalase - metabolism ; Cell Line ; Down-Regulation - drug effects ; Drug resistance ; Drug Resistance, Bacterial ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Gene Expression Regulation, Bacterial - drug effects ; Humans ; Isoniazid - pharmacology ; Microbial Sensitivity Tests ; Microbiology ; Miscellaneous ; Mutation ; Mycobacterium tuberculosis ; Mycobacterium tuberculosis - drug effects ; Mycobacterium tuberculosis - enzymology ; Mycobacterium tuberculosis - genetics ; Protein synthesis ; Tuberculosis ; Tuberculosis - microbiology</subject><ispartof>Molecular microbiology, 2011-03, Vol.79 (6), p.1615-1628</ispartof><rights>2011 Blackwell Publishing Ltd</rights><rights>2015 INIST-CNRS</rights><rights>2011 Blackwell Publishing Ltd.</rights><rights>Copyright Blackwell Publishing Ltd. 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In Mycobacterium tuberculosis, INH is converted to its active form by KatG, a catalase-peroxidase, and attacks InhA, which is essential for the synthesis of mycolic acids. We sequenced furA-katG and fabG1-inhA in 108 INH-resistant (INHr) and 51 INH-susceptible (INHs) isolates, and found three mutations in the furA-katG intergenic region (Intg-⁷a, Inta-¹⁰c and Intg-¹²a) in four of 108 INHr isolates (4%), and the furAc⁴¹t mutation with an amino acid substitution in 18 INHr isolates (17%). These mutations were not found in any of 51 INHs isolates tested. We reconstructed these mutations in isogenic strains to determine whether they conferred INH resistance. We found that the Intg-⁷a, Inta-¹⁰c and Intg-¹²a single mutations in the furA-katG intergenic region decreased katG expression and conferred INH resistance. In contrast, the furAc⁴¹t mutation was not sufficient to confer INH resistance. These results suggested that downregulation of katG is a mechanism of INH resistance in M. tuberculosis and that mutations in the furA-katG intergenic region play a role in this resistance mechanism.</description><subject>Amino acids</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Bacteria</subject><subject>Bacterial Proteins - genetics</subject><subject>Bacterial Proteins - metabolism</subject><subject>Bacteriology</subject><subject>Biological and medical sciences</subject><subject>Catalase - genetics</subject><subject>Catalase - metabolism</subject><subject>Cell Line</subject><subject>Down-Regulation - drug effects</subject><subject>Drug resistance</subject><subject>Drug Resistance, Bacterial</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Bacterial - drug effects</subject><subject>Humans</subject><subject>Isoniazid - pharmacology</subject><subject>Microbial Sensitivity Tests</subject><subject>Microbiology</subject><subject>Miscellaneous</subject><subject>Mutation</subject><subject>Mycobacterium tuberculosis</subject><subject>Mycobacterium tuberculosis - drug effects</subject><subject>Mycobacterium tuberculosis - enzymology</subject><subject>Mycobacterium tuberculosis - genetics</subject><subject>Protein synthesis</subject><subject>Tuberculosis</subject><subject>Tuberculosis - microbiology</subject><issn>0950-382X</issn><issn>1365-2958</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkk-PEyEYxonRuN3Vr6DExHiayp9hBg4ezKrrJtt40E28kRcKlTodKsyk7X56GVvXxItygbz8npcHHhDClMxpGa_Xc8obUTEl5JwRSuekFXU73z9As_uNh2hGlCAVl-zrGTrPeU0I5aThj9EZo6yuBacztHoXd31yq7GDIcQeR4-_w3CF3X6bXM5TKWQMOUcbYHBLvAvDt1KKfYC7sMQFCnmA3jocerw42GjADi6FcYOH0bhkxy4W5Al65KHL7ulpvkC3H95_ufxY3Xy6ur58e1PZYqetuKWSMWmZ9TUxlBkwy9pwkKwhggnjKbVgrWza2kmljGlr4NQT2jhgXnh-gV4d-25T_DG6POhNyNZ1HfQujlkr0tKGcEX_SUrRtJJwogr54i9yHcfUl2sUSNZCFWsFkkfIpphzcl5vU9hAOmhK9BSaXuspGz1lo6fQ9K_Q9L5In536j2bjlvfC3ykV4OUJgGyh86m8d8h_OK5qTtrJw5sjtwudO_y3Ab1YXE-ron9-1HuIGlapnHH7mU2_hirBGiX4T8rwvLQ</recordid><startdate>201103</startdate><enddate>201103</enddate><creator>Ando, Hiroki</creator><creator>Kitao, Tomoe</creator><creator>Miyoshi-Akiyama, Tohru</creator><creator>Kato, Seiya</creator><creator>Mori, Toru</creator><creator>Kirikae, Teruo</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><scope>FBQ</scope><scope>IQODW</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>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201103</creationdate><title>Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis</title><author>Ando, Hiroki ; Kitao, Tomoe ; Miyoshi-Akiyama, Tohru ; Kato, Seiya ; Mori, Toru ; Kirikae, Teruo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5317-3c18228c2cf40b12babd4b3a8260525bf11cacc8674e899bb74a31f016ea2f5f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Amino acids</topic><topic>Antitubercular Agents - pharmacology</topic><topic>Bacteria</topic><topic>Bacterial Proteins - genetics</topic><topic>Bacterial Proteins - metabolism</topic><topic>Bacteriology</topic><topic>Biological and medical sciences</topic><topic>Catalase - genetics</topic><topic>Catalase - metabolism</topic><topic>Cell Line</topic><topic>Down-Regulation - drug effects</topic><topic>Drug resistance</topic><topic>Drug Resistance, Bacterial</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Bacterial - drug effects</topic><topic>Humans</topic><topic>Isoniazid - pharmacology</topic><topic>Microbial Sensitivity Tests</topic><topic>Microbiology</topic><topic>Miscellaneous</topic><topic>Mutation</topic><topic>Mycobacterium tuberculosis</topic><topic>Mycobacterium tuberculosis - drug effects</topic><topic>Mycobacterium tuberculosis - enzymology</topic><topic>Mycobacterium tuberculosis - genetics</topic><topic>Protein synthesis</topic><topic>Tuberculosis</topic><topic>Tuberculosis - microbiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ando, Hiroki</creatorcontrib><creatorcontrib>Kitao, Tomoe</creatorcontrib><creatorcontrib>Miyoshi-Akiyama, Tohru</creatorcontrib><creatorcontrib>Kato, Seiya</creatorcontrib><creatorcontrib>Mori, Toru</creatorcontrib><creatorcontrib>Kirikae, Teruo</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</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>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular microbiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ando, Hiroki</au><au>Kitao, Tomoe</au><au>Miyoshi-Akiyama, Tohru</au><au>Kato, Seiya</au><au>Mori, Toru</au><au>Kirikae, Teruo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis</atitle><jtitle>Molecular microbiology</jtitle><addtitle>Mol Microbiol</addtitle><date>2011-03</date><risdate>2011</risdate><volume>79</volume><issue>6</issue><spage>1615</spage><epage>1628</epage><pages>1615-1628</pages><issn>0950-382X</issn><eissn>1365-2958</eissn><abstract>Isoniazid (INH) is a key agent in the treatment of tuberculosis. In Mycobacterium tuberculosis, INH is converted to its active form by KatG, a catalase-peroxidase, and attacks InhA, which is essential for the synthesis of mycolic acids. We sequenced furA-katG and fabG1-inhA in 108 INH-resistant (INHr) and 51 INH-susceptible (INHs) isolates, and found three mutations in the furA-katG intergenic region (Intg-⁷a, Inta-¹⁰c and Intg-¹²a) in four of 108 INHr isolates (4%), and the furAc⁴¹t mutation with an amino acid substitution in 18 INHr isolates (17%). These mutations were not found in any of 51 INHs isolates tested. We reconstructed these mutations in isogenic strains to determine whether they conferred INH resistance. We found that the Intg-⁷a, Inta-¹⁰c and Intg-¹²a single mutations in the furA-katG intergenic region decreased katG expression and conferred INH resistance. In contrast, the furAc⁴¹t mutation was not sufficient to confer INH resistance. These results suggested that downregulation of katG is a mechanism of INH resistance in M. tuberculosis and that mutations in the furA-katG intergenic region play a role in this resistance mechanism.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>21244531</pmid><doi>10.1111/j.1365-2958.2011.07547.x</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino acids Antitubercular Agents - pharmacology Bacteria Bacterial Proteins - genetics Bacterial Proteins - metabolism Bacteriology Biological and medical sciences Catalase - genetics Catalase - metabolism Cell Line Down-Regulation - drug effects Drug resistance Drug Resistance, Bacterial Fundamental and applied biological sciences. Psychology Gene expression Gene Expression Regulation, Bacterial - drug effects Humans Isoniazid - pharmacology Microbial Sensitivity Tests Microbiology Miscellaneous Mutation Mycobacterium tuberculosis Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - enzymology Mycobacterium tuberculosis - genetics Protein synthesis Tuberculosis Tuberculosis - microbiology |
| title | Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis |
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