Missense mutations in the catalase‐peroxidase gene, katG, are associated with isoniazid resistance in Mycobacterium tuberculosis

Molecular Microbiology - Tập 15 Số 2 - Trang 235-245 - 1995
Béate Heym1, Pedro M. Alzari2, Nadine Honoré1, Stewart T. Cole1
1Unite de Génétique Moléculaire Bactérienne
2Unité de Immunologie Structurale. Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France.

Tóm tắt

SummaryThe toxicity of the powerful anti‐tuberculosis drug isoniazid (INH) is believed to be mediated by the haem‐containing enzyme catalase‐peroxidase, encoded by the katG gene of Mycobacterium tuberculosis. Compelling evidence for this was obtained by studying a panel of INH‐resistant clinical isolates using a novel strategy based on the polymerase chain reaction and single‐strand‐conformation polymorphism analysis (PCR‐SSCP) to detect mutations in katG. In most cases INH resistance was associated with missense mutations while in a small number of strains the gene had been completely, or partially, deleted. The missense mutations fell into two groups, the larger of which contained several independent mutations that affected the N‐terminal peroxidase domain of the protein, resulting in the production of a catalase peroxidase with strongly reduced enzyme activity and increased heat lability. The effects of these substitutions could be interpreted by means of molecular modelling using the crystal structure of the related enzyme cytochrome c peroxidase from yeast as a template. The second group comprises a frequently occurring amino acid substitution and a single mutation that are both located in the C‐terminal domain but do not noticeably alter either enzyme activity or heat stability.

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Molecular Microbiology

Tập 15 Số 2

235-245

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