ArticleAntimicrobial agents and chemotherapy2007
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.
Article in Antimicrobial agents and chemotherapy, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34 citing papers in PubMed, 74 citations in OpenAlex.
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- Determination of frequency of spontaneous resistance for gepotidacin and levofloxacin against a collection of gram-positive and gram-negative organisms.Antimicrobial agents and chemotherapy · 2026Article
- Advancing Topoisomerase Research Using DNA Nanotechnology.Small methods · 2025Review
- Design, Synthesis, Anti-Varicella-Zoster and Antimicrobial Activity of (Isoxazolidin-3-yl)Phosphonate Conjugates of N1-Functionalised Quinazoline-2,4-Diones.Molecules (Basel, Switzerland) · 2022Article
- Discovery of Quinazoline-2,4(1Molecules (Basel, Switzerland) · 2022Article
- Allele-specific collateral and fitness effects determine the dynamics of fluoroquinolone resistance evolution.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.RSC medicinal chemistry · 2020Article
- Facilely accessible quinoline derivatives as potent antibacterial agents.Bioorganic & medicinal chemistry · 2018Article
- Development and characterisation of highly antibiotic resistant Bartonella bacilliformis mutants.Scientific reports · 2016Article
- Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance.Cold Spring Harbor perspectives in medicine · 2016Review
- Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones.Nucleic acids research · 2016Article
- Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- A "Double-Edged" Scaffold: Antitumor Power within the Antibacterial Quinolone.Current medicinal chemistry · 2016Review
- Protective effect of Qnr on agents other than quinolones that target DNA gyrase.Antimicrobial agents and chemotherapy · 2015Article
- Insights into the mechanism of inhibition of novel bacterial topoisomerase inhibitors from characterization of resistant mutants of Staphylococcus aureus.Antimicrobial agents and chemotherapy · 2015Article
- Characterization of the novel DNA gyrase inhibitor AZD0914: low resistance potential and lack of cross-resistance in Neisseria gonorrhoeae.Antimicrobial agents and chemotherapy · 2015Article
- Bacillus anthracis GrlAV96A topoisomerase IV, a quinolone resistance mutation that does not affect the water-metal ion bridge.Antimicrobial agents and chemotherapy · 2014Article
- Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions.ACS chemical biology · 2013Article
- Quinazoline-2,4(1H, 3H)-diones inhibit the growth of multiple human tumor cell lines.Molecular diversity · 2013Article
- Topoisomerase IV-quinolone interactions are mediated through a water-metal ion bridge: mechanistic basis of quinolone resistance.Nucleic acids research · 2013Article
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11 authors at 2 institutions in 1 country.
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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.
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