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JAC Advance Access originally published online on June 19, 2008
Journal of Antimicrobial Chemotherapy 2008 62(4):720-729; doi:10.1093/jac/dkn261
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Resistance mapping and mode of action of a novel class of antibacterial anthranilic acids: evidence for disruption of cell wall biosynthesis

John E. Mott1,2, Bailin A. Shaw3, James F. Smith3, Paul D. Bonin1,3, Donna L. Romero1,4, Keith R. Marotti1,5 and Alita A. Miller1,3,*

1 Infectious Diseases Biology, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, MI 49007, USA 2 Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA 3 Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA 4 Pharma-Vation Consulting LLC, 1201 Turnberry Ridge Court, Chesterfield, MO 63005, USA 5 Pfizer Veterinary Medicine, 301 Henrietta Street, Kalamazoo, MI 49007, USA

Received 16 March 2008; returned 3 April 2008; revised 29 May 2008; accepted 2 June 2008

* Correspondence address. Antibacterials Biology, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. Tel: +1-860-686-6808; Fax: +1-860-715-4693; E-mail: alita.a.miller{at}pfizer.com

Objectives: The aim of this study was to characterize the mechanism of action of a novel class of bacterial protein synthesis inhibitors identified in a high-throughput coupled transcription–translation assay.

Methods: Evaluation of the cross-resistance to antibiotics with known mechanisms of action, resistance mapping and biochemical characterization of a novel class of antibacterial anthranilic acids was performed.

Results: No cross-resistance to established classes of antibiotics was found. Resistance was mapped to SA1575, an essential, integral membrane protein predicted to be involved in polysaccharide biosynthesis. Biochemical analysis demonstrated the inhibition of cell wall biosynthesis.

Conclusions: This novel class of antibacterial anthranilic acids inhibits cell wall biosynthesis. Resistance mapped to SA1575, which may represent a novel target for antibacterial drug discovery.

Keywords: Staphylococcus aureus , antibiotic discovery , HTS


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