Inhibition of a Mycobacterium tuberculosis β-Ketoacyl ACP synthase by isoniazid

Khisimuzi Mdluli, Richard A. Slayden, Ya Qi Zhu, Srinivas Ramaswamy, Xi Pan, David Mead, Deborah D. Crane, James M. Musser, Clifton E. Barry

Research output: Contribution to journalArticle

355 Scopus citations

Abstract

Although isoniazid (isonicortinic 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 in 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.

Original languageEnglish (US)
Pages (from-to)1607-1610
Number of pages4
JournalScience
Volume280
Issue number5369
DOIs
StatePublished - Jun 5 1998

ASJC Scopus subject areas

  • General

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