Inhibition of a Mycobacterium tuberculosis β-Ketoacyl ACP Synthase by Isoniazid-Reference-Cited by-同舟云学术

Inhibition of a Mycobacterium tuberculosis β-Ketoacyl ACP Synthase by Isoniazid

Published:1998-06-05 Issue:5369 Volume:280 Page:1607-1610
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Mdluli Khisimuzi¹²,Slayden Richard A.¹²,Zhu YaQi¹²,Ramaswamy Srinivas¹²,Pan Xi¹²,Mead David¹²,Crane Deborah D.¹²,Musser James M.¹²,Barry Clifton E.¹²

Affiliation:

1. K. Mdluli, R. A. Slayden, Y. Zhu, D. Mead, D. D. Crane, C. E. Barry III, Tuberculosis Research Unit, Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health, Hamilton, MT 59840, USA.

2. S. Ramaswamy, X. Pan, J. M. Musser, Institute for the Study of Human Bacterial Pathogenesis, Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

Although isoniazid (isonicotinic acid hydrazide, INH) is widely used for the treatment of tuberculosis, its molecular target has remained elusive. In response to INH treatment, saturated hexacosanoic acid (C26:0) accumulated on a 12-kilodalton acyl carrier protein (AcpM) that normally carried mycolic acid precursors as long as C50. A protein species purified from INH-treated Mycobacterium tuberculosis was shown to consist of a covalent complex of INH, AcpM, and a β-ketoacyl acyl carrier protein synthase, KasA. Amino acid–altering mutations in the KasA protein were identified in INH-resistant patient isolates that lacked other mutations associated with resistance to this drug.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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