Research articles

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

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  • 1.Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom;Chemistry Research Laboratory, Department of Organic Chemistry, University of Oxford, Oxford OX1 3QL, United Kingdom;Current address: Structure-Based Drug Design Team, Sections of Structural Biology and Cancer Therapeutics, Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, United Kingdom; 2.Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom;Current address: Institute of Structural and Molecular Biology, Department of Biological Science, Birkbeck, University of London, London WC1E 7HX, United Kingdom; 3.Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom;Chemistry Research Laboratory, Department of Organic Chemistry, University of Oxford, Oxford OX1 3QL, United Kingdom; 4.Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom; 5.Chemistry Research Laboratory, Department of Organic Chemistry, University of Oxford, Oxford OX1 3QL, United Kingdom; 6.School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; 7.Tuberculosis Immunology Group, Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection and Immunity, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom;

Published date: 01 Jan 2010

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.

Cite this article

Isaac M. Westwood, Sanjib Bhakta, Angela J. Russell, Elizabeth Fullam, Akane Kawamura, Matthew C. Anderton, Edith Sim, Andrew W. Mulvaney, Richard J. Vickers, Stephen G. Davies, Veemal Bhowruth, Gurdyal S. Besra, Ajit Lalvani, . Identification of arylamine N -acetyltransferase inhibitors as an approach towards novel anti-tuberculars[J]. Protein & Cell, 2010 , 1(1) : 82 -95 . DOI: 10.1007/s13238-010-0006-1

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