JAC Advance Access originally published online on February 24, 2009
Journal of Antimicrobial Chemotherapy 2009 63(5):928-936; doi:10.1093/jac/dkp031
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Original research |
Inhibition of MptpB phosphatase from Mycobacterium tuberculosis impairs mycobacterial survival in macrophages
1 Faculty of Life Sciences, University of Manchester, Manchester, UK 2 Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, USA 3 Abbott Laboratories, Abbott Park, IL 60064, USA 4 STFC Daresbury Laboratory, Warrington WA4 4AD, UK
Received 24 September 2008; returned 12 December 2008; revised 23 December 2008; accepted 22 January 2009
* Corresponding author. Tel: +44-161-275-7794; Fax: +44-161-275-5082; E-mail: lydia.tabernero{at}manchester.ac.uk
Objectives: The secreted Mycobacterium tuberculosis protein tyrosine phosphatase (MptpB) is a virulence factor for M. tuberculosis and contributes to its survival within host macrophages. The aim of this study was to identify potent selective inhibitors of MptpB and to determine the efficacy of these compounds in mycobacterium-infected macrophages.
Methods: The inhibitory effect of a small library of compounds on MptpB was first examined in vitro. The efficacy of these compounds was further examined in mycobacterium-infected macrophages.
Results: We have identified a new family of double-site isoxazole-based compounds that are potent selective inhibitors of MptpB. Importantly, the inhibitors substantially reduce mycobacterial survival in infected macrophages. In contrast with current anti-tubercular drugs, these MptpB inhibitors do not have bactericidal action but rather, severely impair mycobacterial growth within macrophages. Docking analysis suggests a double-site binding mechanism of inhibition with the isoxazole head in the active site and a salicylate group in a secondary binding pocket that is a unique structural feature of MptpB.
Conclusions: These results provide the first evidence that inhibition of phosphatases can be exploited against mycobacterial infections. The cell activity of the inhibitors together with the lack of MptpB human orthologues suggests a strong potential for these compounds to be developed as drug candidates against tuberculosis and promises a new therapeutic strategy to tackle clearance and reduce the persistence of M. tuberculosis infection.
Keywords: inhibitors , docking , infection , BCG , tyrosine kinase
Present address: Sirtris Pharmaceuticals, Inc., Cambridge, MA, USA.
Present address: Ambit Biosciences, San Diego, CA, USA.
In memoriam. ¶ L. T. and J. S. C. contributed equally to the production of this manuscript.