This Article Full Text Full Text (PDF) Other Versions of this Article: AAC.01321-06v1 51/4/1191    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Huband, M. D. Articles by Gracheck, S. J. Search for Related Content PubMed PubMed Citation Articles by Huband, M. D. Articles by Gracheck, S. J.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, April 2007, p. 1191-1201, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01321-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Activities of PD 0305970 and PD 0326448, New Bacterial Gyrase/Topoisomerase Inhibitors with Potent Antibacterial Activities versus Multidrug-Resistant Gram-Positive and Fastidious Organism Groups

Department of Antibacterial Biology, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105,¹ Detroit Medical Center, 3990 John R Road, Detroit, Michigan 48201,² Department of Chemistry, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105,³ Pfizer Global Research and Development, 10770 Science Center Drive, La Jolla, California 92121⁴

Received 23 October 2006/ Returned for modification 21 November 2006/ Accepted 11 January 2007

PD 0305970 and PD 0326448 are new bacterial gyrase and topoisomerase inhibitors (quinazoline-2,4-diones) that possess outstanding in vitro and in vivo activities against a wide spectrum of bacterial species including quinolone- and multidrug-resistant gram-positive and fastidious organism groups. The respective MICs (µg/ml) for PD 0305970 capable of inhibiting 90% of bacterial strains tested ranged from 0.125 to 0.5 versus staphylococci, 0.03 to 0.06 versus streptococci, 0.25 to 2 versus enterococci, and 0.25 to 0.5 versus Moraxella catarrhalis, Haemophilus influenzae, Listeria monocytogenes, Legionella pneumophila, and Neisseria spp. PD 0326448 MIC₉₀s were generally twofold higher versus these same organism groups. Comparative quinolone MIC₉₀ values were 4- to 512-fold higher than those of PD 0305970. In testing for frequency of resistance, PD 0305970 and levofloxacin showed low levels of development of spontaneous resistant mutants versus both Staphylococcus aureus and Streptococcus pneumoniae. Unlike quinolones, which target primarily gyrA and parC, analysis of resistant mutants in S. pneumoniae indicates that the likely targets of PD 0305970 are gyrB and parE. PD 0305970 demonstrated rapid bactericidal activity by in vitro time-kill testing versus streptococci. This bactericidal activity carried over to in vivo testing, where PD 0305970 and PD 0326448 displayed outstanding Streptococcus pyogenes 50% protective doses (PD₅₀s) (oral dosing) of 0.7 and 3.6 mg/kg, respectively (ciprofloxacin and levofloxacin PD₅₀s were >100 and 17.7 mg/kg, respectively). PD 0305970 was also potent in a pneumococcal pneumonia mouse infection model (PD₅₀ = 3.2 mg/kg) and was 22-fold more potent than levofloxacin.

Published ahead of print on 29 January 2007.