The Journal of Experimental Medicine
Torrey Pines Biolabs
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published online 26 April 2004 doi:10.1084/jem.20031956
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 9, 1191-1199
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 330K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bhakta, S.
Right arrow Articles by Sim, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bhakta, S.
Right arrow Articles by Sim, E.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
Arylamine N-Acetyltransferase Is Required for Synthesis of Mycolic Acids and Complex Lipids in Mycobacterium bovis BCG and Represents a Novel Drug Target

Sanjib Bhakta1, Gurdyal S. Besra3, Anna M. Upton1, Tanya Parish5, Carolyn Sholto-Douglas-Vernon1, Kevin J.C. Gibson3, Stuart Knutton4, Siamon Gordon2, Rosangela P. daSilva2, Matthew C. Anderton1, and Edith Sim1

1 Department of Pharmacology and 2 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
3 Department of Biosciences and 4 Institute of Child Health, University of Birmingham, Birmingham B4 6NH, UK
5 Department of Medical Microbiology, Barts and the London, Queen Mary's School of Medicine and Dentistry, London E1 2AD, UK

Address correspondence to Edith Sim, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. Phone: 44-1865-271883; Fax: 44-1865-271853; email: edith.sim{at}pharm.ox.ac.uk

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.

Key Words: isoniazid • macrophage • Mycobacterium tuberculosis • cell wall • metabolism

A. Upton's present address is The Rockefeller University, 1230 York Avenue, New York, NY 10021.

Abbreviations used in this paper: ADC, albumin-dextrose-catalase; CF, cord factor; GMM, glucose monomycolate; INH, isoniazid; MK, menaquinone; NAT, arylamine N-acetyltransferase; OADC, oleic acid–ADC; ORF, open reading frame; PDIM, phthiocerol dimycocerosate; SEM, scanning electron microscopy; TEM, transmission electron microscopy; TLC, thin layer chromatography.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS