title: 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.
abstract: 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 (microg/ml) for PD 0305970 capable of inhibiting>or=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.
authors.affiliation: Department of Antibacterial Biology, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. Michael.Huband@Pfizer.com
authors.forename: Michael D
authors.initials: MD
authors.lastname: Huband
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cohen
authors.forename: Margaret
authors.initials: M
authors.lastname: Zurack
authors.forename: Debra L
authors.initials: DL
authors.lastname: Hanna
authors.forename: Laura A
authors.initials: LA
authors.lastname: Skerlos
authors.forename: Mark C
authors.initials: MC
authors.lastname: Sulavik
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Gibson
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Gage
authors.forename: Edmund
authors.initials: E
authors.lastname: Ellsworth
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stier
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gracheck
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D018432:Drug Resistance, Multiple; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D008826:Microbial Sensitivity Tests; D011759:Pyrrolidines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
chemical_list: C521524:3-amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione; C521525:7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione; D000900:Anti-Bacterial Agents; D011759:Pyrrolidines; D052999:Quinazolinones; D059005:Topoisomerase II Inhibitors