8 Jan 2013

Discovery of a Novel Class of Boron-based Antibacterials with Activity against Gram-negative Bacteria (Antimicrob Agents Chemother., abstract, edited)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Discovery of a Novel Class of Boron-based Antibacterials with Activity against Gram-negative Bacteria

Vincent Hernandez 1, Thibaut Crépin 2, Andrés Palencia 2, Stephen Cusack 2, Tsutomu Akama 1, Stephen J. Baker 1, Wei Bu 1, Lisa Feng 1, Yvonne R. Freund 1, Liang Liu 1, Maliwan Meewan 1, Manisha Mohan 1, Weimin Mao 1, Fernando L. Rock 1, Holly Sexton 1, Anita Sheoran 1, Yanchen Zhang 1, Yong-Kang Zhang 1, Yasheen Zhou 1, James A. Nieman 3, Mahipal Reddy Anugula 3, El Mehdi Keramane 3, Kingsley Savariraj 3, D. Shekhar Reddy 3, Rashmi Sharma 3, Rajendra Subedi 3, Rajeshwar Singh 3, Ann O'Leary 4, Nerissa L. Simon 5, Peter L. De Marsh 5, Shazad Mushtaq 6, Marina Warner 6, David M. Livermore 6,7, M. R. K. Alley 1,* and Jacob J. Plattner 1

Author Affiliations: 1Anacor Pharmaceuticals Inc, 1020 E Meadow Circle, Palo Alto, CA 94303 2European Molecular Biology Laboratory, Grenoble Outstation, and Unit of Virus Host-Cell Interactions, UJF-EMBL-CNRS, UMI 3265, 6 rue Jules Horowitz, BP181, 38042 Grenoble Cedex 9, France 3NAEJA Pharmaceuticals Inc., 4290-91A Street, Edmonton, AB, Canada, T6E 5V2 4Ricerca, 7528 Auburn Road, Concord, OH 44077, USA 5Antibacterial Discovery Performance Unit, GlaxoSmithKline, Collegeville, PA 19426 6Antibiotic Resistance Monitoring & Reference Laboratory, Health Protection Agency Microbiology Services-Colindale, 61 Colindale Avenue, London NW9 5EQ, UK 7Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK

 

ABSTRACT

Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and P. aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases as well as Pseudomonas aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against Escherichia coli and P. aeruginosa in murine thigh-infection models, which suggest this novel class of antibacterials has the potential to addresses this unmet medical need.

 

FOOTNOTES

* Corresponding author. Anacor Pharmaceuticals Inc, 1020 E Meadow Circle, Palo Alto, CA 94303. E-mail: dalley@anacor.com

Copyright © 2013, American Society for Microbiology. All Rights Reserved.

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