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Tan, Christopher M.; Gill, Charles J.; Wu, Jin; Toussaint, Nathalie; Yin, Jingjun; Tsuchiya, Takayuki; Garlisi, Charles G.; Kaelin, David; Meinke, Peter T.; Miesel, Lynn; Olsen, David B.; Lagrutta, Armando; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Oohata, Kouhei; Takeuchi, Tomoko; Shibue, Taku; Takano, Hisashi; Nishimura, Akinori; Fukuda, Yasumichi; Singh, Sheo B.

In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

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  • Medientyp: E-Artikel
  • Titel: In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase
  • Beteiligte: Tan, Christopher M.; Gill, Charles J.; Wu, Jin; Toussaint, Nathalie; Yin, Jingjun; Tsuchiya, Takayuki; Garlisi, Charles G.; Kaelin, David; Meinke, Peter T.; Miesel, Lynn; Olsen, David B.; Lagrutta, Armando; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Oohata, Kouhei; Takeuchi, Tomoko; Shibue, Taku; Takano, Hisashi; Nishimura, Akinori; Fukuda, Yasumichi; Singh, Sheo B.
  • Erschienen: American Society for Microbiology, 2016
  • Erschienen in: Antimicrobial Agents and Chemotherapy
  • Sprache: Englisch
  • DOI: 10.1128/aac.00619-16
  • ISSN: 0066-4804; 1098-6596
  • Schlagwörter: Infectious Diseases ; Pharmacology (medical) ; Pharmacology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>ABSTRACT</jats:title> <jats:p> Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and <jats:italic>in vivo</jats:italic> characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Staphylococcus aureus</jats:named-content> and <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Escherichia coli</jats:named-content> and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence <jats:italic>in vitro</jats:italic> at concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> . </jats:p>
  • Zugangsstatus: Freier Zugang