Arylamine N-acetyltransferase is required for synthesis of mycolic acids and complex lipids in Mycobacterium bovis BCG and represents a novel drug target.
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.
Bhakta
Sanjib
S
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Besra
Gurdyal S
GS
Upton
Anna M
AM
Parish
Tanya
T
Sholto-Douglas-Vernon
Carolyn
C
Gibson
Kevin J C
KJ
Knutton
Stuart
S
Gordon
Siamon
S
DaSilva
Rosangela P
RP
Anderton
Matthew C
MC
Sim
Edith
E
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D001500:BCG Vaccine; D017931:DNA Primers; D017353:Gene Deletion; D005798:Genes, Bacterial / Q000235:genetics; D007538:Isoniazid / Q000494:pharmacology*; D008055:Lipids / Q000096:biosynthesis*; D009163:Mycobacterium bovis / Q000187:drug effects / Q000201:enzymology*; D009171:Mycolic Acids / Q000378:metabolism*; D016366:Open Reading Frames; D011994:Recombinant Proteins / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D001500:BCG Vaccine; D017931:DNA Primers; D008055:Lipids; D009171:Mycolic Acids; D011994:Recombinant Proteins; D001191:Arylamine N-Acetyltransferase; D007538:Isoniazid