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Journal of Bacteriology, February 1999, p. 1343-1347, Vol. 181, No. 4
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cloning and Characterization of Arylamine N-Acetyltransferase Genes from Mycobacterium smegmatis and Mycobacterium tuberculosis: Increased Expression Results in Isoniazid Resistance

Mark Payton,1 Roy Auty,1 Rupika Delgoda,1 Martin Everett,2 and Edith Sim1,*

Department of Pharmacology, University of Oxford, Oxford OX1 3QT,1 and Research and Development, Glaxo-Wellcome plc, Stevenage, Hertfordshire SG1 2NY,2 United Kingdom

Received 9 September 1998/Accepted 3 December 1998

Arylamine N-acetyltransferases (NATs) are found in many eukaryotic organisms, including humans, and have previously been identified in the prokaryote Salmonella typhimurium. NATs from many sources acetylate the antitubercular drug isoniazid and so inactivate it. nat genes were cloned from Mycobacterium smegmatis and Mycobacterium tuberculosis, and expressed in Escherichia coli and M. smegmatis. The induced M. smegmatis NAT catalyzes the acetylation of isoniazid. A monospecific antiserum raised against pure NAT from S. typhimurium recognizes NAT from M. smegmatis and cross-reacts with recombinant NAT from M. tuberculosis. Overexpression of mycobacterial nat genes in E. coli results in predominantly insoluble recombinant protein; however, with M. smegmatis as the host using the vector pACE-1, NAT proteins from M. tuberculosis and M. smegmatis are soluble. M. smegmatis transformants induced to express the M. tuberculosis nat gene in culture demonstrated a threefold higher resistance to isoniazid. We propose that NAT in mycobacteria could have a role in acetylating, and hence inactivating, isoniazid.

* Corresponding author. Mailing address: Department of Pharmacology, University of Oxford, Mansfield Rd., Oxford OX1 3QT, United Kingdom. Phone: (44 1865) 271596. Fax: (44 1865) 271853. E-mail: esim{at}worf.molbiol.ox.ac.uk.

Journal of Bacteriology, February 1999, p. 1343-1347, Vol. 181, No. 4
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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