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Antimicrobial Agents and Chemotherapy, April 2006, p. 1228-1237, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1228-1237.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Characterization of the Antibacterial Spectrum of Novel Bacterial Type II Topoisomerase Inhibitors of the Aminobenzimidazole Class

Nagraj Mani, Christian H. Gross, Jonathan D. Parsons, Brian Hanzelka, Ute Müh, Steve Mullin, Yusheng Liao, Anne-Laure Grillot, Dean Stamos, Paul S. Charifson, and Trudy H. Grossman^*

Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139

Received 9 October 2005/ Returned for modification 5 December 2005/ Accepted 18 January 2006

Antibiotics with novel mechanisms of action are becoming increasingly important in the battle against bacterial resistance to all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics. Here we present the characterization of two members of a new class of synthetic bacterial topoII ATPase inhibitors: VRT-125853 and VRT-752586. These aminobenzimidazole compounds were potent inhibitors of both DNA gyrase and topoIV and had excellent antibacterial activities against a wide spectrum of problematic pathogens responsible for both nosocomial and community-acquired infections, including staphylococci, streptococci, enterococci, and mycobacteria. Consistent with the novelty of their structures and mechanisms of action, antibacterial potency was unaffected by commonly encountered resistance phenotypes, including fluoroquinolone resistance. In time-kill assays, VRT-125853 and VRT-752586 were bactericidal against Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, and Haemophilus influenzae, causing 3-log reductions in viable cells within 24 h. Finally, similar to the fluoroquinolones, relatively low frequencies of spontaneous resistance to VRT-125853 and VRT-752586 were found, a property consistent with their in vitro dual-targeting activities.

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* Corresponding author. Mailing address: Vertex Pharmaceuticals, 130 Waverly Street, Cambridge MA 02139. Phone: (617) 444-6252. Fax: (617) 444-6210. E-mail: trudy_grossman{at}vrtx.com.

Present address: Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts.

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Antimicrobial Agents and Chemotherapy, April 2006, p. 1228-1237, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1228-1237.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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