InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II
Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, 205 route de Narbonne, 31077 Toulouse cedex, France 1 Author for correspondence: A. Quémard. Tel: +33 5 61 17 55 76. Fax: +33 5 61 17 59 94. e-mail: annaik{at}ipbs.fr Most drug-resistant clinical isol...
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| Veröffentlicht in: | Microbiology (Society for General Microbiology) 2000-02, Vol.146 (2), p.289-296 |
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| creator | Marrakchi, Hedia Laneelle, Gilbert Quemard, Annaik |
| description | Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, 205 route de Narbonne, 31077 Toulouse cedex, France 1
Author for correspondence: A. Quémard. Tel: +33 5 61 17 55 76. Fax: +33 5 61 17 59 94. e-mail: annaik{at}ipbs.fr
Most drug-resistant clinical isolates of the tubercle bacillus are resistant to isoniazid, a first-line antituberculous drug. This antibiotic was shown to act on Mycobacterium tuberculosis by inhibiting a 2- trans -enoyl-acyl carrier protein reductase, called InhA. However, the exact role played by InhA in mycobacteria remained unclear. A mycobacterial enzyme fraction containing InhA was isolated. It displays a long-chain fatty acid elongation activity with the characteristic properties described for the FAS-II (fatty acid synthetase II) system. Inhibition of this activity by InhA inhibitors, namely isoniazid, hexadecynoyl-CoA or octadecynoyl-CoA, showed that InhA belongs to the FAS-II system. Moreover, the InhA inhibitors also blocked the biosynthesis of mycolic acids, which are major lipids of the mycobacterial envelope. The data strongly suggest that isoniazid acts on the mycobacterial cell wall by preventing the FAS-II system from producing long-chain fatty acid precursors for mycolic acid biosynthesis.
Keywords: InhA, fatty acid synthetase II, mycolic acid biosynthesis, isoniazid target, Mycobacterium Abbreviations: ACP, acyl carrier protein; FAS, fatty acid synthetase; FES, fatty acid elongation system; INH, isoniazid (isonicotinic acid hydrazide); NE, 2-(2,3-naphthalimino)ethyl; NE-OTf, 2-(2,3-naphthalimino)ethyl trifluoromethanesulphonate; p CMS, p -chloromercuriphenylsulphonic acid |
| doi_str_mv | 10.1099/00221287-146-2-289 |
| format | Article |
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Author for correspondence: A. Quémard. Tel: +33 5 61 17 55 76. Fax: +33 5 61 17 59 94. e-mail: annaik{at}ipbs.fr
Most drug-resistant clinical isolates of the tubercle bacillus are resistant to isoniazid, a first-line antituberculous drug. This antibiotic was shown to act on Mycobacterium tuberculosis by inhibiting a 2- trans -enoyl-acyl carrier protein reductase, called InhA. However, the exact role played by InhA in mycobacteria remained unclear. A mycobacterial enzyme fraction containing InhA was isolated. It displays a long-chain fatty acid elongation activity with the characteristic properties described for the FAS-II (fatty acid synthetase II) system. Inhibition of this activity by InhA inhibitors, namely isoniazid, hexadecynoyl-CoA or octadecynoyl-CoA, showed that InhA belongs to the FAS-II system. Moreover, the InhA inhibitors also blocked the biosynthesis of mycolic acids, which are major lipids of the mycobacterial envelope. The data strongly suggest that isoniazid acts on the mycobacterial cell wall by preventing the FAS-II system from producing long-chain fatty acid precursors for mycolic acid biosynthesis.
Keywords: InhA, fatty acid synthetase II, mycolic acid biosynthesis, isoniazid target, Mycobacterium Abbreviations: ACP, acyl carrier protein; FAS, fatty acid synthetase; FES, fatty acid elongation system; INH, isoniazid (isonicotinic acid hydrazide); NE, 2-(2,3-naphthalimino)ethyl; NE-OTf, 2-(2,3-naphthalimino)ethyl trifluoromethanesulphonate; p CMS, p -chloromercuriphenylsulphonic acid</description><identifier>ISSN: 1350-0872</identifier><identifier>EISSN: 1465-2080</identifier><identifier>DOI: 10.1099/00221287-146-2-289</identifier><identifier>PMID: 10708367</identifier><language>eng</language><publisher>Reading: Soc General Microbiol</publisher><subject>2-trans-enoyl-acyl carrier protein reductase ; Antibacterial agents ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antitubercular Agents - pharmacology ; Bacterial Proteins ; Bacteriology ; Biogenesis of cell structures, supramolecular organization ; Biological and medical sciences ; Blotting, Western ; Cell Wall - drug effects ; Cell Wall - metabolism ; Fatty Acid Synthases - metabolism ; fatty-acid synthase II ; Fundamental and applied biological sciences. Psychology ; InhA protein ; isoniazid ; Isoniazid - pharmacology ; Medical sciences ; Microbiology ; Mycobacterium smegmatis - drug effects ; Mycobacterium smegmatis - enzymology ; Mycobacterium tuberculosis ; Mycolic Acids - metabolism ; Oxidoreductases - antagonists & inhibitors ; Oxidoreductases - metabolism ; Pharmacology. Drug treatments</subject><ispartof>Microbiology (Society for General Microbiology), 2000-02, Vol.146 (2), p.289-296</ispartof><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c502t-5a742a6546378fa6b40d91baf4891c71bd17985a5dc5c618e96b7648bf6a3b5e3</citedby><cites>FETCH-LOGICAL-c502t-5a742a6546378fa6b40d91baf4891c71bd17985a5dc5c618e96b7648bf6a3b5e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,27907,27908</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1328376$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10708367$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Marrakchi, Hedia</creatorcontrib><creatorcontrib>Laneelle, Gilbert</creatorcontrib><creatorcontrib>Quemard, Annaik</creatorcontrib><title>InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II</title><title>Microbiology (Society for General Microbiology)</title><addtitle>Microbiology</addtitle><description>Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, 205 route de Narbonne, 31077 Toulouse cedex, France 1
Author for correspondence: A. Quémard. Tel: +33 5 61 17 55 76. Fax: +33 5 61 17 59 94. e-mail: annaik{at}ipbs.fr
Most drug-resistant clinical isolates of the tubercle bacillus are resistant to isoniazid, a first-line antituberculous drug. This antibiotic was shown to act on Mycobacterium tuberculosis by inhibiting a 2- trans -enoyl-acyl carrier protein reductase, called InhA. However, the exact role played by InhA in mycobacteria remained unclear. A mycobacterial enzyme fraction containing InhA was isolated. It displays a long-chain fatty acid elongation activity with the characteristic properties described for the FAS-II (fatty acid synthetase II) system. Inhibition of this activity by InhA inhibitors, namely isoniazid, hexadecynoyl-CoA or octadecynoyl-CoA, showed that InhA belongs to the FAS-II system. Moreover, the InhA inhibitors also blocked the biosynthesis of mycolic acids, which are major lipids of the mycobacterial envelope. The data strongly suggest that isoniazid acts on the mycobacterial cell wall by preventing the FAS-II system from producing long-chain fatty acid precursors for mycolic acid biosynthesis.
Keywords: InhA, fatty acid synthetase II, mycolic acid biosynthesis, isoniazid target, Mycobacterium Abbreviations: ACP, acyl carrier protein; FAS, fatty acid synthetase; FES, fatty acid elongation system; INH, isoniazid (isonicotinic acid hydrazide); NE, 2-(2,3-naphthalimino)ethyl; NE-OTf, 2-(2,3-naphthalimino)ethyl trifluoromethanesulphonate; p CMS, p -chloromercuriphenylsulphonic acid</description><subject>2-trans-enoyl-acyl carrier protein reductase</subject><subject>Antibacterial agents</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Bacterial Proteins</subject><subject>Bacteriology</subject><subject>Biogenesis of cell structures, supramolecular organization</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Cell Wall - drug effects</subject><subject>Cell Wall - metabolism</subject><subject>Fatty Acid Synthases - metabolism</subject><subject>fatty-acid synthase II</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>InhA protein</subject><subject>isoniazid</subject><subject>Isoniazid - pharmacology</subject><subject>Medical sciences</subject><subject>Microbiology</subject><subject>Mycobacterium smegmatis - drug effects</subject><subject>Mycobacterium smegmatis - enzymology</subject><subject>Mycobacterium tuberculosis</subject><subject>Mycolic Acids - metabolism</subject><subject>Oxidoreductases - antagonists & inhibitors</subject><subject>Oxidoreductases - metabolism</subject><subject>Pharmacology. 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Antiinfectious agents. Antiparasitic agents</topic><topic>Antitubercular Agents - pharmacology</topic><topic>Bacterial Proteins</topic><topic>Bacteriology</topic><topic>Biogenesis of cell structures, supramolecular organization</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Cell Wall - drug effects</topic><topic>Cell Wall - metabolism</topic><topic>Fatty Acid Synthases - metabolism</topic><topic>fatty-acid synthase II</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>InhA protein</topic><topic>isoniazid</topic><topic>Isoniazid - pharmacology</topic><topic>Medical sciences</topic><topic>Microbiology</topic><topic>Mycobacterium smegmatis - drug effects</topic><topic>Mycobacterium smegmatis - enzymology</topic><topic>Mycobacterium tuberculosis</topic><topic>Mycolic Acids - metabolism</topic><topic>Oxidoreductases - antagonists & inhibitors</topic><topic>Oxidoreductases - metabolism</topic><topic>Pharmacology. Drug treatments</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Marrakchi, Hedia</creatorcontrib><creatorcontrib>Laneelle, Gilbert</creatorcontrib><creatorcontrib>Quemard, Annaik</creatorcontrib><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>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><jtitle>Microbiology (Society for General Microbiology)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Marrakchi, Hedia</au><au>Laneelle, Gilbert</au><au>Quemard, Annaik</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II</atitle><jtitle>Microbiology (Society for General Microbiology)</jtitle><addtitle>Microbiology</addtitle><date>2000-02-01</date><risdate>2000</risdate><volume>146</volume><issue>2</issue><spage>289</spage><epage>296</epage><pages>289-296</pages><issn>1350-0872</issn><eissn>1465-2080</eissn><abstract>Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, 205 route de Narbonne, 31077 Toulouse cedex, France 1
Author for correspondence: A. Quémard. Tel: +33 5 61 17 55 76. Fax: +33 5 61 17 59 94. e-mail: annaik{at}ipbs.fr
Most drug-resistant clinical isolates of the tubercle bacillus are resistant to isoniazid, a first-line antituberculous drug. This antibiotic was shown to act on Mycobacterium tuberculosis by inhibiting a 2- trans -enoyl-acyl carrier protein reductase, called InhA. However, the exact role played by InhA in mycobacteria remained unclear. A mycobacterial enzyme fraction containing InhA was isolated. It displays a long-chain fatty acid elongation activity with the characteristic properties described for the FAS-II (fatty acid synthetase II) system. Inhibition of this activity by InhA inhibitors, namely isoniazid, hexadecynoyl-CoA or octadecynoyl-CoA, showed that InhA belongs to the FAS-II system. Moreover, the InhA inhibitors also blocked the biosynthesis of mycolic acids, which are major lipids of the mycobacterial envelope. The data strongly suggest that isoniazid acts on the mycobacterial cell wall by preventing the FAS-II system from producing long-chain fatty acid precursors for mycolic acid biosynthesis.
Keywords: InhA, fatty acid synthetase II, mycolic acid biosynthesis, isoniazid target, Mycobacterium Abbreviations: ACP, acyl carrier protein; FAS, fatty acid synthetase; FES, fatty acid elongation system; INH, isoniazid (isonicotinic acid hydrazide); NE, 2-(2,3-naphthalimino)ethyl; NE-OTf, 2-(2,3-naphthalimino)ethyl trifluoromethanesulphonate; p CMS, p -chloromercuriphenylsulphonic acid</abstract><cop>Reading</cop><pub>Soc General Microbiol</pub><pmid>10708367</pmid><doi>10.1099/00221287-146-2-289</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 2-trans-enoyl-acyl carrier protein reductase Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Antitubercular Agents - pharmacology Bacterial Proteins Bacteriology Biogenesis of cell structures, supramolecular organization Biological and medical sciences Blotting, Western Cell Wall - drug effects Cell Wall - metabolism Fatty Acid Synthases - metabolism fatty-acid synthase II Fundamental and applied biological sciences. Psychology InhA protein isoniazid Isoniazid - pharmacology Medical sciences Microbiology Mycobacterium smegmatis - drug effects Mycobacterium smegmatis - enzymology Mycobacterium tuberculosis Mycolic Acids - metabolism Oxidoreductases - antagonists & inhibitors Oxidoreductases - metabolism Pharmacology. Drug treatments |
| title | InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II |
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