Arylamine N-Acetyltransferase Is Required for Synthesis of Mycolic Acids and Complex Lipids in Mycobacterium bovis BCG and Represents a Novel Drug Target

Sanjib Bhakta, Gurdyal S. Besra, Anna M. Upton, Tanya Parish, Carolyn Sholto-Douglas-Vernon, Kevin J.C. Gibson, Stuart Knutton, Siamon Gordon, Rosangela P. DaSilva, Matthew C. Anderton, Edith Sim*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

97 Scopus citations

Abstract

Mycolic acids represent a major component of the unique cell wall of mycobacteria. Mycolic acid biosynthesis is inhibited by isoniazid, a key frontline antitubercular drug that is inactivated by mycobacterial and human arylamine N-acetyltransferase (NAT). We show that an in-frame deletion of Mycobacterium bovis BCG nat results in delayed entry into log phase, altered morphology, altered cell wall lipid composition, and increased intracellular killing by macrophages. In particular, deletion of nat perturbs biosynthesis of mycolic acids and their derivatives and increases susceptibility of M. bovis BCG to antibiotics that permeate the cell wall. Phenotypic traits are fully complemented by introduction of Mycobacterium tuberculosis nat. We infer from our findings that NAT is critical to normal mycolic acid synthesis and hence other derivative cell wall components and represents a novel target for antituberculosis therapy. In addition, this is the first report of an endogenous role for NAT in mycobacteria.

Original languageEnglish
Pages (from-to)1191-1199
Number of pages9
JournalJournal of Experimental Medicine
Volume199
Issue number9
DOIs
StatePublished - 03 05 2004
Externally publishedYes

Keywords

  • Cell wall
  • Isoniazid
  • Macrophage
  • Metabolism
  • Mycobacterium tuberculosis

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