Biochemical and Genetic Data Suggest that InhA Is Not the Primary Target for Activated Isoniazid in Mycobacterium tuberculosis
An examination of the pattern of lipid biosynthetic responses to isoniazid (INH) treatment of Mycobacterium tuberculosis and Mycobacterium smegmatis suggests that the mode of action of activated INH differs between these 2 organisms. Transformation of M. smegmatis with inhA on a plasmid construct co...
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| Veröffentlicht in: | The Journal of infectious diseases 1996-11, Vol.174 (5), p.1085-1090 |
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| container_title | The Journal of infectious diseases |
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| creator | Mdluli, Khisimuzi Sherman, David R. Hickey, Mark J. Kreiswirth, Barry N. Morris, Sheldon Stover, C. Kendall Barry, Clifton E. |
| description | An examination of the pattern of lipid biosynthetic responses to isoniazid (INH) treatment of Mycobacterium tuberculosis and Mycobacterium smegmatis suggests that the mode of action of activated INH differs between these 2 organisms. Transformation of M. smegmatis with inhA on a plasmid construct conferred high-level resistance to INH, while the same construct failed to confer resistance upon M. tuberculosis. The inhA region from 2 clinical isolates whose resistance has been attributed to changes in the upstream promoter region has been cloned and was not sufficient to impart INH resistance to the level of the parent strain on sensitive M. tuberculosis. These putative mutant promoter elements appear to elevate expression levels of gene fusion reporter constructs, suggesting some noncausal connection between the observed mutations and the lipid metabolism of drug-resistant organisms. These results suggest that InhA is not the major target for activated INH in M. tuberculosis. |
| doi_str_mv | 10.1093/infdis/174.5.1085 |
| format | Article |
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Kendall ; Barry, Clifton E.</creator><creatorcontrib>Mdluli, Khisimuzi ; Sherman, David R. ; Hickey, Mark J. ; Kreiswirth, Barry N. ; Morris, Sheldon ; Stover, C. Kendall ; Barry, Clifton E.</creatorcontrib><description>An examination of the pattern of lipid biosynthetic responses to isoniazid (INH) treatment of Mycobacterium tuberculosis and Mycobacterium smegmatis suggests that the mode of action of activated INH differs between these 2 organisms. Transformation of M. smegmatis with inhA on a plasmid construct conferred high-level resistance to INH, while the same construct failed to confer resistance upon M. tuberculosis. The inhA region from 2 clinical isolates whose resistance has been attributed to changes in the upstream promoter region has been cloned and was not sufficient to impart INH resistance to the level of the parent strain on sensitive M. tuberculosis. These putative mutant promoter elements appear to elevate expression levels of gene fusion reporter constructs, suggesting some noncausal connection between the observed mutations and the lipid metabolism of drug-resistant organisms. These results suggest that InhA is not the major target for activated INH in M. tuberculosis.</description><identifier>ISSN: 0022-1899</identifier><identifier>EISSN: 1537-6613</identifier><identifier>DOI: 10.1093/infdis/174.5.1085</identifier><identifier>PMID: 8896513</identifier><identifier>CODEN: JIDIAQ</identifier><language>eng</language><publisher>Chicago, IL: The University of Chicago Press</publisher><subject>Antibacterial agents ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antitubercular Agents - pharmacology ; Bacterial Proteins - genetics ; Biological and medical sciences ; Biotransformation ; Drug Resistance, Microbial ; Fatty acids ; Genetic loci ; Genetic mutation ; Genetic vectors ; Isoniazid - metabolism ; Isoniazid - pharmacology ; Lipids ; Lipids - biosynthesis ; Major Articles ; Medical sciences ; Mutation ; Mycobacterium smegmatis ; Mycobacterium tuberculosis ; Mycobacterium tuberculosis - drug effects ; Operator regions ; Oxidoreductases ; Pharmacology. 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Kendall</creatorcontrib><creatorcontrib>Barry, Clifton E.</creatorcontrib><title>Biochemical and Genetic Data Suggest that InhA Is Not the Primary Target for Activated Isoniazid in Mycobacterium tuberculosis</title><title>The Journal of infectious diseases</title><addtitle>J Infect Dis</addtitle><description>An examination of the pattern of lipid biosynthetic responses to isoniazid (INH) treatment of Mycobacterium tuberculosis and Mycobacterium smegmatis suggests that the mode of action of activated INH differs between these 2 organisms. Transformation of M. smegmatis with inhA on a plasmid construct conferred high-level resistance to INH, while the same construct failed to confer resistance upon M. tuberculosis. The inhA region from 2 clinical isolates whose resistance has been attributed to changes in the upstream promoter region has been cloned and was not sufficient to impart INH resistance to the level of the parent strain on sensitive M. tuberculosis. These putative mutant promoter elements appear to elevate expression levels of gene fusion reporter constructs, suggesting some noncausal connection between the observed mutations and the lipid metabolism of drug-resistant organisms. These results suggest that InhA is not the major target for activated INH in M. tuberculosis.</description><subject>Antibacterial agents</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Bacterial Proteins - genetics</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Drug Resistance, Microbial</subject><subject>Fatty acids</subject><subject>Genetic loci</subject><subject>Genetic mutation</subject><subject>Genetic vectors</subject><subject>Isoniazid - metabolism</subject><subject>Isoniazid - pharmacology</subject><subject>Lipids</subject><subject>Lipids - biosynthesis</subject><subject>Major Articles</subject><subject>Medical sciences</subject><subject>Mutation</subject><subject>Mycobacterium smegmatis</subject><subject>Mycobacterium tuberculosis</subject><subject>Mycobacterium tuberculosis - drug effects</subject><subject>Operator regions</subject><subject>Oxidoreductases</subject><subject>Pharmacology. Drug treatments</subject><subject>Plasmids</subject><subject>Promoter regions</subject><subject>Promoter Regions, Genetic</subject><subject>Tuberculosis</subject><issn>0022-1899</issn><issn>1537-6613</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU9vEzEQxS0EKqHwATggWQhx29Zer_8dQ4E0KBQkilT1YjleO3HYXRfbiygHPjuONgSJ00jzfvM0Mw-A5xidYSTJuR9c69M55s0ZLR1BH4AZpoRXjGHyEMwQqusKCykfgycp7RBCDWH8BJwIIRnFZAZ-v_HBbG3vje6gHlq4sIPN3sC3Omv4ZdxsbMowb3WGy2E7h8sEr8K-YeHn6Hsd7-G1jhuboQsRzk32P3S2beHC4PUv30I_wI_3Jqy1yTb6sYd5XNtoxi4kn56CR053yT471FPw9f2764vLavVpsbyYryrTCJarmjVEW9dw2bTlMkGpZMIhihrqhG1aQeoWc8alEdIQ1xhHjEa8drS2jOk1OQWvJ9-7GL6P5STV-2Rs1-nBhjEpTAWWlKICvvwP3IUxDmU3VddElk8LXiA8QSaGlKJ16m76hcJI7YNRUzCq4IqqfTBl5sXBeFz3tj1OHJIo-quDrlPJwkU9mOLwF6sbTpCU_2x2KYd4lAnCdfERRa8m3adsfx51Hb8pxgmn6vLmVl3drNiHhaTqlvwBVgGwFQ</recordid><startdate>19961101</startdate><enddate>19961101</enddate><creator>Mdluli, Khisimuzi</creator><creator>Sherman, David R.</creator><creator>Hickey, Mark J.</creator><creator>Kreiswirth, Barry N.</creator><creator>Morris, Sheldon</creator><creator>Stover, C. Kendall</creator><creator>Barry, Clifton E.</creator><general>The University of Chicago Press</general><general>University of Chicago Press</general><general>Oxford University Press</general><scope>BSCLL</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>K9.</scope><scope>NAPCQ</scope><scope>7QL</scope><scope>C1K</scope></search><sort><creationdate>19961101</creationdate><title>Biochemical and Genetic Data Suggest that InhA Is Not the Primary Target for Activated Isoniazid in Mycobacterium tuberculosis</title><author>Mdluli, Khisimuzi ; Sherman, David R. ; Hickey, Mark J. ; Kreiswirth, Barry N. ; Morris, Sheldon ; Stover, C. 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Kendall</au><au>Barry, Clifton E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Biochemical and Genetic Data Suggest that InhA Is Not the Primary Target for Activated Isoniazid in Mycobacterium tuberculosis</atitle><jtitle>The Journal of infectious diseases</jtitle><addtitle>J Infect Dis</addtitle><date>1996-11-01</date><risdate>1996</risdate><volume>174</volume><issue>5</issue><spage>1085</spage><epage>1090</epage><pages>1085-1090</pages><issn>0022-1899</issn><eissn>1537-6613</eissn><coden>JIDIAQ</coden><abstract>An examination of the pattern of lipid biosynthetic responses to isoniazid (INH) treatment of Mycobacterium tuberculosis and Mycobacterium smegmatis suggests that the mode of action of activated INH differs between these 2 organisms. Transformation of M. smegmatis with inhA on a plasmid construct conferred high-level resistance to INH, while the same construct failed to confer resistance upon M. tuberculosis. 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| ispartof | The Journal of infectious diseases, 1996-11, Vol.174 (5), p.1085-1090 |
| issn | 0022-1899 1537-6613 |
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| source | MEDLINE; JSTOR Archive Collection A-Z Listing; Oxford University Press Journals All Titles (1996-Current) |
| subjects | Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Antitubercular Agents - pharmacology Bacterial Proteins - genetics Biological and medical sciences Biotransformation Drug Resistance, Microbial Fatty acids Genetic loci Genetic mutation Genetic vectors Isoniazid - metabolism Isoniazid - pharmacology Lipids Lipids - biosynthesis Major Articles Medical sciences Mutation Mycobacterium smegmatis Mycobacterium tuberculosis Mycobacterium tuberculosis - drug effects Operator regions Oxidoreductases Pharmacology. Drug treatments Plasmids Promoter regions Promoter Regions, Genetic Tuberculosis |
| title | Biochemical and Genetic Data Suggest that InhA Is Not the Primary Target for Activated Isoniazid in Mycobacterium tuberculosis |
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