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Identification of arylamine N-acetyltransferase inhibitors as an approach towards novel anti-tuberculars.
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Westwood, Isaac M., Bhakta, Sanjib, Russell, Angela J., Fullam, Elizabeth, Anderton, Matthew C., Kawamura, Akane, Mulvaney, Andrew W., Vickers, Richard J., Bhowruth, Veemal, Besra, Gurdyal S., Lalvani, Ajit, Davies, Stephen G. and Sim, Edith (2010) Identification of arylamine N-acetyltransferase inhibitors as an approach towards novel anti-tuberculars. Protein & Cell, Volume 1 (Number 1). pp. 82-95. doi:10.1007/s13238-010-0006-1 ISSN 1674-8018 .
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Official URL: http://dx.doi.org/10.1007/s13238-010-0006-1
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.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Journal or Publication Title: | Protein & Cell | ||||
Publisher: | Springer | ||||
ISSN: | 1674-8018 | ||||
Official Date: | 18 March 2010 | ||||
Dates: |
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Volume: | Volume 1 | ||||
Number: | Number 1 | ||||
Page Range: | pp. 82-95 | ||||
DOI: | 10.1007/s13238-010-0006-1 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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