Protein & Cell

, Volume 1, Issue 1, pp 82–95 | Cite as

Identification of arylamine N-acetyltransferase inhibitors as an approach towards novel anti-tuberculars

  • Isaac M. Westwood
  • Sanjib Bhakta
  • Angela J. Russell
  • Elizabeth Fullam
  • Matthew C. Anderton
  • Akane Kawamura
  • Andrew W. Mulvaney
  • Richard J. Vickers
  • Veemal Bhowruth
  • Gurdyal S. Besra
  • Ajit Lalvani
  • Stephen G. Davies
  • Edith Sim
Research Article

Abstract

New anti-tubercular drugs and drug targets are urgently needed to reduce the time for treatment and also to identify agents that will be effective against Mycobacterium tuberculosis persisting intracellularly. Mycobacteria have a unique cell wall. Deletion of the gene for arylamine N-acetyltransferase (NAT) decreases mycobacterial cell wall lipids, particularly the distinctive mycolates, and also increases antibiotic susceptibility and killing within macrophage of Mycobacterium bovis BCG. The nat gene and its associated gene cluster are almost identical in sequence in M. bovis BCG and M. tuberculosis. The gene cluster is essential for intracellular survival of mycobacteria. We have therefore used pure NAT protein for high-throughput screening to identify several classes of small molecules that inhibit NAT activity. Here, we characterize one class of such molecules—triazoles—in relation to its effects on the target enzyme and on both M. bovis BCG and M. tuberculosis. The most potent triazole mimics the effects of deletion of the nat gene on growth, lipid disruption and intracellular survival. We also present the structure-activity relationship between NAT inhibition and effects on mycobacterial growth, and use ligand-protein analysis to give further insight into the structure-activity relationships. We conclude that screening a chemical library with NAT protein yields compounds that have high potential as anti-tubercular agents and that the inhibitors will allow further exploration of the biochemical pathway in which NAT is involved.

Keywords

N-acetyltransferase Mycobacterium tuberculosis triazoles screening 

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Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Isaac M. Westwood
    • 1
    • 2
  • Sanjib Bhakta
    • 1
  • Angela J. Russell
    • 1
    • 2
  • Elizabeth Fullam
    • 1
    • 2
  • Matthew C. Anderton
    • 1
  • Akane Kawamura
    • 1
    • 2
  • Andrew W. Mulvaney
    • 2
  • Richard J. Vickers
    • 2
  • Veemal Bhowruth
    • 3
  • Gurdyal S. Besra
    • 3
  • Ajit Lalvani
    • 4
  • Stephen G. Davies
    • 2
  • Edith Sim
    • 1
  1. 1.Department of PharmacologyUniversity of OxfordOxfordUK
  2. 2.Chemistry Research Laboratory, Department of Organic ChemistryUniversity of OxfordOxfordUK
  3. 3.School of BiosciencesUniversity of BirminghamEdgbaston, BirminghamUK
  4. 4.Tuberculosis Immunology Group, Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection and ImmunityImperial College London, Norfolk PlaceLondonUK
  5. 5.Structure-Based Drug Design Team, Sections of Structural Biology and Cancer Therapeutics, Institute of Cancer ResearchChester Beatty LaboratoriesLondonUK
  6. 6.Institute of Structural and Molecular Biology, Department of Biological Science, BirkbeckUniversity of LondonLondonUK

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