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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.


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