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Antimicrobial Agents and Chemotherapy, February 2005, p. 708-720, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.708-720.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Altered NADH/NAD⁺ Ratio Mediates Coresistance to Isoniazid and Ethionamide in Mycobacteria

Catherine Vilchèze,¹ Torin R. Weisbrod,¹ Bing Chen,¹ Laurent Kremer,^2, Manzour H. Hazbón,³ Feng Wang,⁴ David Alland,³ James C. Sacchettini,⁴ and William R. Jacobs Jr.^1*

Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York,¹ Laboratoire des Mécanismes Moléculaires de la Pathogénie Microbienne, INSERM, Institut Pasteur de Lille, Lille, France,² Division 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,³ Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas⁴

Received 5 August 2004/ Returned for modification 9 September 2004/ Accepted 27 September 2004

The front-line antituberculosis drug isoniazid (INH) and the related drug ethionamide (ETH) are prodrugs that upon activation inhibit the synthesis of mycolic acids, leading to bactericidal activity. Coresistance to INH and ETH can be mediated by dominant mutations in the target gene inhA, encoding an enoyl-ACP reductase, or by recessive mutations in ndh, encoding a type II NADH dehydrogenase (NdhII). To address the mechanism of resistance mediated by the latter, we have isolated novel ndh mutants of Mycobacterium smegmatis and Mycobacterium bovis BCG. The M. smegmatis ndh mutants were highly resistant to INH and ETH, while the M. bovis BCG mutants had low-level resistance to INH and ETH. All mutants had defects in NdhII activity resulting in an increase in intracellular NADH/NAD⁺ ratios. Increasing NADH levels were shown to protect InhA against inhibition by the INH-NAD adduct formed upon INH activation. We conclude that ndh mutations mediate a novel mechanism of resistance by increasing the NADH cellular concentration, which competitively inhibits the binding of INH-NAD or ETH-NAD adduct to InhA.

Present address: Dynamique des Interactions Membranaires, CNRS UMR 5539, Université de Montpellier II, 34095 Montpellier, France.

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