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, Sanjib
AU - Besra, Gurdyal S.
AU - Upton, Anna M.
AU - Parish, Tanya
AU - Sholto-Douglas-Vernon, Carolyn
AU - Gibson, Kevin J.C.
AU - Knutton, Stuart
AU - Gordon, Siamon
AU - DaSilva, Rosangela P.
AU - Anderton, Matthew C.
AU - Sim, Edith
PY - 2004/5/3
Y1 - 2004/5/3
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 - Cell wall
KW - Isoniazid
KW - Macrophage
KW - Metabolism
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 - 文章
C2 - 15117974
AN - SCOPUS:2442466919
SN - 0022-1007
VL - 199
SP - 1191
EP - 1199
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 9
ER -