Arylamine N-acetyltransferase is required for synthesis of mycolic acids and complex lipids in Mycobacterium bovis BCG and represents a novel drug target

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Arylamine N-acetyltransferase is required for synthesis of mycolic acids and complex lipids in Mycobacterium bovis BCG and represents a novel drug target. / Bhakta, S; Besra, Gurdyal; Upton, AM; Parish, T; Sholto-Douglas-Vernon, C; Gibson, KJC; Knutton, Stuart.

In: The Journal of Experimental Medicine, Vol. 199, 26.04.2004, p. 1191-1199.

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@article{ead75137e7694a759ea09bd912b0a6c6,
title = "Arylamine N-acetyltransferase is required for synthesis of mycolic acids and complex lipids in Mycobacterium bovis BCG and represents a novel drug target",
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.",
keywords = "isoniazid, metabolism, cell wall, macrophage, Mycobacterium tuberculosis",
author = "S Bhakta and Gurdyal Besra and AM Upton and T Parish and C Sholto-Douglas-Vernon and KJC Gibson and Stuart Knutton",
year = "2004",
month = apr,
day = "26",
doi = "10.1084/jem.20031956",
language = "English",
volume = "199",
pages = "1191--1199",
journal = "The Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",

}

RIS

TY - JOUR

T1 - Arylamine N-acetyltransferase is required for synthesis of mycolic acids and complex lipids in Mycobacterium bovis BCG and represents a novel drug target

AU - Bhakta, S

AU - Besra, Gurdyal

AU - Upton, AM

AU - Parish, T

AU - Sholto-Douglas-Vernon, C

AU - Gibson, KJC

AU - Knutton, Stuart

PY - 2004/4/26

Y1 - 2004/4/26

N2 - 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.

AB - 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.

KW - isoniazid

KW - metabolism

KW - cell wall

KW - macrophage

KW - Mycobacterium tuberculosis

UR - http://www.scopus.com/inward/record.url?scp=2442466919&partnerID=8YFLogxK

U2 - 10.1084/jem.20031956

DO - 10.1084/jem.20031956

M3 - Article

C2 - 15117974

VL - 199

SP - 1191

EP - 1199

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

SN - 0022-1007

ER -