Christopher M. Tan , a , Charles J. Gill a , Jin Wu a , Nathalie Toussaint a , Jingjun Yin b , Takayuki Tsuchiya c , Charles G. Garlisi a , David Kaelin a , Peter T. Meinke b , Lynn Miesel a , David B. Olsen c , Armando Lagrutta c , Hideyuki Fukuda d , Ryuta Kishii d , Masaya Takei d , Kouhei Oohata d , Tomoko Takeuchi d , Taku Shibue d , Hisashi Takano d , Akinori Nishimura d , Yasumichi Fukuda d , Sheo B. Singh , a
22 July 2016
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 in vivo 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 Staphylococcus aureus and Escherichia coli 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 in vitro 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 in vitro and in vivo.