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Mechanisms of Action: Physiological Effects

Mycobacterium tuberculosis Dihydrofolate Reductase Is Not a Target Relevant to the Antitubercular Activity of Isoniazid

Feng Wang, Paras Jain, Gulcin Gulten, Zhen Liu, Yicheng Feng, Krishna Ganesula, Alifiya S. Motiwala, Thomas R. Ioerger, David Alland, Catherine Vilchèze, William R. Jacobs Jr., James C. Sacchettini
Feng Wang
1Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128
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Paras Jain
2Department of Microbiology and Immunology and the Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461
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Gulcin Gulten
1Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128
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Zhen Liu
1Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128
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Yicheng Feng
1Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128
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Krishna Ganesula
3Department of Computer Science and Engineering, Texas A&M University, College Station, Texas 77843-3112
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Alifiya S. Motiwala
4Division of Infectious Diseases, Department of Medicine, and the Ruy V. Lourenço Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103
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Thomas R. Ioerger
3Department of Computer Science and Engineering, Texas A&M University, College Station, Texas 77843-3112
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  • For correspondence: ioerger@cs.tamu.edu
David Alland
4Division of Infectious Diseases, Department of Medicine, and the Ruy V. Lourenço Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103
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Catherine Vilchèze
2Department of Microbiology and Immunology and the Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461
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William R. Jacobs Jr.
2Department of Microbiology and Immunology and the Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461
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James C. Sacchettini
1Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128
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DOI: 10.1128/AAC.00453-10
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ABSTRACT

Mycobacterium tuberculosis enoyl-acyl-ACP reductase (InhA) has been demonstrated to be the primary target of isoniazid (INH). Recently, it was postulated that M. tuberculosis dihydrofolate reductase (DHFR) is also a target of INH, based on the findings that a 4R-INH-NADP adduct synthesized from INH by a nonenzymatic approach showed strong inhibition of DHFR in vitro, and overexpression of M. tuberculosis dfrA in M. smegmatis conferred a 2-fold increase of resistance to INH. In the present study, a plasmid expressing M. tuberculosis dfrA was transformed into M. smegmatis and M. tuberculosis strains, respectively. The transformant strains were tested for their resistance to INH. Compared to the wild-type strains, overexpression of dfrA in M. smegmatis and M. tuberculosis did not confer any resistance to INH based on the MIC values. Similar negative results were obtained with 14 other overexpressed proteins that have been proposed to bind some form of INH-NAD(P) adduct. An Escherichia coli cell-based system was designed that allowed coexpression of both M. tuberculosis katG and dfrA genes in the presence of INH. The DHFR protein isolated from the experimental sample was not found bound with any INH-NADP adduct by enzyme inhibition assay and mass spectroscopic analysis. We also used whole-genome sequencing to determine whether polymorphisms in dfrA could be detected in six INH-resistant clinical isolates known to lack mutations in inhA and katG, but no such mutations were found. The dfrA overexpression experiments, together with the biochemical and sequencing studies, conclusively demonstrate that DHFR is not a target relevant to the antitubercular activity of INH.

  • Copyright © 2010 American Society for Microbiology
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Mycobacterium tuberculosis Dihydrofolate Reductase Is Not a Target Relevant to the Antitubercular Activity of Isoniazid
Feng Wang, Paras Jain, Gulcin Gulten, Zhen Liu, Yicheng Feng, Krishna Ganesula, Alifiya S. Motiwala, Thomas R. Ioerger, David Alland, Catherine Vilchèze, William R. Jacobs Jr., James C. Sacchettini
Antimicrobial Agents and Chemotherapy Aug 2010, 54 (9) 3776-3782; DOI: 10.1128/AAC.00453-10

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Mycobacterium tuberculosis Dihydrofolate Reductase Is Not a Target Relevant to the Antitubercular Activity of Isoniazid
Feng Wang, Paras Jain, Gulcin Gulten, Zhen Liu, Yicheng Feng, Krishna Ganesula, Alifiya S. Motiwala, Thomas R. Ioerger, David Alland, Catherine Vilchèze, William R. Jacobs Jr., James C. Sacchettini
Antimicrobial Agents and Chemotherapy Aug 2010, 54 (9) 3776-3782; DOI: 10.1128/AAC.00453-10
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KEYWORDS

antitubercular agents
isoniazid
Mycobacterium tuberculosis
Tetrahydrofolate Dehydrogenase

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