This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Miesel, L.
Right arrow Articles by Jacobs, W. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Miesel, L.
Right arrow Articles by Jacobs, W. R., Jr.

 Previous Article  |  Next Article 

J Bacteriol, May 1998, p. 2459-2467, Vol. 180, No. 9
0021-9193/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

NADH Dehydrogenase Defects Confer Isoniazid Resistance and Conditional Lethality in Mycobacterium smegmatis

Lynn Miesel,1 Torin R. Weisbrod,1 Jovita A. Marcinkeviciene,2 Robert Bittman,3 and William R. Jacobs Jr.1,*

Department of Microbiology and Immunology1 and Department of Biochemistry,2 Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461, and Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, New York 113673

Received 31 October 1997/Accepted 23 February 1998

Isoniazid (INH) is a highly effective drug used in the treatment and prophylaxis of Mycobacterium tuberculosis infections. Resistance to INH in clinical isolates has been correlated with mutations in the inhA, katG, and ahpC genes. In this report, we describe a new mechanism for INH resistance in Mycobacterium smegmatis. Mutations that reduce NADH dehydrogenase activity (Ndh; type II) cause multiple phenotypes, including (i) coresistance to INH and a related drug, ethionamide; (ii) thermosensitive lethality; and (iii) auxotrophy. These phenotypes are corrected by expression of one of two enzymes: NADH dehydrogenase and the NADH-dependent malate dehydrogenase of the M. tuberculosis complex. The genetic data presented here indicate that defects in NADH oxidation cause all of the mutant traits and that an increase in the NADH/NAD+ ratio confers INH resistance.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2888. Fax: (718) 518-0366. E-mail: jacobs{at}aecom.yu.edu.

J Bacteriol, May 1998, p. 2459-2467, Vol. 180, No. 9
0021-9193/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Mogi, T., Murase, Y., Mori, M., Shiomi, K., Omura, S., Paranagama, M. P., Kita, K. (2009). Polymyxin B Identified as an Inhibitor of Alternative NADH Dehydrogenase and Malate: Quinone Oxidoreductase from the Gram-positive Bacterium Mycobacterium smegmatis. J Biochem 146: 491-499 [Abstract] [Full Text]  
  • Ho, Y. M., Sun, Y.-J., Wong, S.-Y., Lee, A. S. G. (2009). Contribution of dfrA and inhA Mutations to the Detection of Isoniazid-Resistant Mycobacterium tuberculosis Isolates. Antimicrob. Agents Chemother. 53: 4010-4012 [Abstract] [Full Text]  
  • Karakousis, P. C., Williams, E. P., Bishai, W. R. (2008). Altered expression of isoniazid-regulated genes in drug-treated dormant Mycobacterium tuberculosis. J Antimicrob Chemother 61: 323-331 [Abstract] [Full Text]  
  • Siddiqi, S., Takhar, P., Baldeviano, C., Glover, W., Zhang, Y. (2007). Isoniazid Induces Its Own Resistance in Nonreplicating Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 51: 2100-2104 [Abstract] [Full Text]  
  • Guo, H., Seet, Q., Denkin, S., Parsons, L., Zhang, Y. (2006). Molecular characterization of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from the USA.. J Med Microbiol 55: 1527-1531 [Abstract] [Full Text]  
  • Hazbon, M. H., Brimacombe, M., Bobadilla del Valle, M., Cavatore, M., Guerrero, M. I., Varma-Basil, M., Billman-Jacobe, H., Lavender, C., Fyfe, J., Garcia-Garcia, L., Leon, C. I., Bose, M., Chaves, F., Murray, M., Eisenach, K. D., Sifuentes-Osornio, J., Cave, M. D., Ponce de Leon, A., Alland, D. (2006). Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant Mycobacterium tuberculosis.. Antimicrob. Agents Chemother. 50: 2640-2649 [Abstract] [Full Text]  
  • Yano, T., Li, L.-S., Weinstein, E., Teh, J.-S., Rubin, H. (2006). Steady-state Kinetics and Inhibitory Action of Antitubercular Phenothiazines on Mycobacterium tuberculosis Type-II NADH-Menaquinone Oxidoreductase (NDH-2). J. Biol. Chem. 281: 11456-11463 [Abstract] [Full Text]  
  • Leung, E. T. Y., Ho, P. L., Yuen, K. Y., Woo, W. L., Lam, T. H., Kao, R. Y., Seto, W. H., Yam, W. C. (2006). Molecular Characterization of Isoniazid Resistance in Mycobacterium tuberculosis: Identification of a Novel Mutation in inhA. Antimicrob. Agents Chemother. 50: 1075-1078 [Abstract] [Full Text]  
  • Tran, S. L., Cook, G. M. (2005). The F1Fo-ATP Synthase of Mycobacterium smegmatis Is Essential for Growth. J. Bacteriol. 187: 5023-5028 [Abstract] [Full Text]  
  • Weinstein, E. A., Yano, T., Li, L.-S., Avarbock, D., Avarbock, A., Helm, D., McColm, A. A., Duncan, K., Lonsdale, J. T., Rubin, H. (2005). Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs. Proc. Natl. Acad. Sci. USA 102: 4548-4553 [Abstract] [Full Text]  
  • Vilcheze, C., Weisbrod, T. R., Chen, B., Kremer, L., Hazbon, M. H., Wang, F., Alland, D., Sacchettini, J. C., Jacobs, W. R. Jr. (2005). Altered NADH/NAD+ Ratio Mediates Coresistance to Isoniazid and Ethionamide in Mycobacteria. Antimicrob. Agents Chemother. 49: 708-720 [Abstract] [Full Text]  
  • Raymond, J. B., Mahapatra, S., Crick, D. C., Pavelka, M. S. Jr. (2005). Identification of the namH Gene, Encoding the Hydroxylase Responsible for the N-Glycolylation of the Mycobacterial Peptidoglycan. J. Biol. Chem. 280: 326-333 [Abstract] [Full Text]  
  • Boshoff, H. I. M., Myers, T. G., Copp, B. R., McNeil, M. R., Wilson, M. A., Barry, C. E. III (2004). The Transcriptional Responses of Mycobacterium tuberculosis to Inhibitors of Metabolism: NOVEL INSIGHTS INTO DRUG MECHANISMS OF ACTION. J. Biol. Chem. 279: 40174-40184 [Abstract] [Full Text]  
  • Kremer, L., Dover, L. G., Morbidoni, H. R., Vilcheze, C., Maughan, W. N., Baulard, A., Tu, S.-C., Honore, N., Deretic, V., Sacchettini, J. C., Locht, C., Jacobs, W. R. Jr., Besra, G. S. (2003). Inhibition of InhA Activity, but Not KasA Activity, Induces Formation of a KasA-containing Complex in Mycobacteria. J. Biol. Chem. 278: 20547-20554 [Abstract] [Full Text]  
  • Ramaswamy, S. V., Reich, R., Dou, S.-J., Jasperse, L., Pan, X., Wanger, A., Quitugua, T., Graviss, E. A. (2003). Single Nucleotide Polymorphisms in Genes Associated with Isoniazid Resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 47: 1241-1250 [Abstract] [Full Text]  
  • Helling, R. B. (2002). Speed versus Efficiency in Microbial Growth and the Role of Parallel Pathways. J. Bacteriol. 184: 1041-1045 [Abstract] [Full Text]  
  • Sassetti, C. M., Boyd, D. H., Rubin, E. J. (2001). Comprehensive identification of conditionally essential genes in mycobacteria. Proc. Natl. Acad. Sci. USA 10.1073/pnas.231275498v1 [Abstract] [Full Text]  
  • Lee, A. S. G., Teo, A. S. M., Wong, S.-Y. (2001). Novel Mutations in ndh in Isoniazid-Resistant Mycobacterium tuberculosis Isolates. Antimicrob. Agents Chemother. 45: 2157-2159 [Abstract] [Full Text]  
  • Molenaar, D., van der Rest, M. E., Drysch, A., Yücel, R. (2000). Functions of the Membrane-Associated and Cytoplasmic Malate Dehydrogenases in the Citric Acid Cycle of Corynebacterium glutamicum. J. Bacteriol. 182: 6884-6891 [Abstract] [Full Text]  
  • Vilchèze, C., Morbidoni, H. R., Weisbrod, T. R., Iwamoto, H., Kuo, M., Sacchettini, J. C., Jacobs, W. R. Jr. (2000). Inactivation of the inhA-Encoded Fatty Acid Synthase II (FASII) Enoyl-Acyl Carrier Protein Reductase Induces Accumulation of the FASI End Products and Cell Lysis of Mycobacterium smegmatis. J. Bacteriol. 182: 4059-4067 [Abstract] [Full Text]  
  • Lee, A. S. G., Lim, I. H. K., Tang, L. L. H., Telenti, A., Wong, S. Y. (1999). Contribution of kasA Analysis to Detection of Isoniazid-Resistant Mycobacterium tuberculosis in Singapore. Antimicrob. Agents Chemother. 43: 2087-2089 [Abstract] [Full Text]  
  • McMurry, L. M., McDermott, P. F., Levy, S. B. (1999). Genetic Evidence that InhA of Mycobacterium smegmatis Is a Target for Triclosan. Antimicrob. Agents Chemother. 43: 711-713 [Abstract] [Full Text]  
  • Chen, P., Bishai, W. R. (1998). Novel Selection for Isoniazid (INH) Resistance Genes Supports a Role for NAD+-Binding Proteins in Mycobacterial INH Resistance. Infect. Immun. 66: 5099-5106 [Abstract] [Full Text]  
  • Telenti, A (1998). Genetics and pulmonary medicine bullet  5: Genetics of drug resistant tuberculosis. Thorax 53: 793-797 [Full Text]  
  • Sassetti, C. M., Boyd, D. H., Rubin, E. J. (2001). Comprehensive identification of conditionally essential genes in mycobacteria. Proc. Natl. Acad. Sci. USA 98: 12712-12717 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»