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      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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          Abstract

          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.

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          Author and article information

          Journal
          Antimicrob Agents Chemother
          Antimicrob. Agents Chemother
          aac
          aac
          AAC
          Antimicrobial Agents and Chemotherapy
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0066-4804
          1098-6596
          31 May 2016
          22 July 2016
          August 2016
          : 60
          : 8
          : 4830-4839
          Affiliations
          [a ]Merck Research Laboratories, Kenilworth, New Jersey, USA
          [b ]Merck Research Laboratories, Rahway, New Jersey, USA
          [c ]Merck Research Laboratories, West Point, Pennsylvania, USA
          [d ]Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan
          Author notes
          Address correspondence to Christopher M. Tan, christopher_tan@ 123456merck.com , or Sheo B. Singh, sheo.singh.215@ 123456gmail.com .
          [*]

          Present address: Sheo B. Singh, SBS Pharma Consulting LLC, Edison, New Jersey, USA.

          Citation Tan CM, Gill CJ, Wu J, Toussaint N, Yin J, Tsuchiya T, Garlisi CG, Kaelin D, Meinke PT, Miesel L, Olsen DB, Lagrutta A, Fukuda H, Kishii R, Takei M, Oohata K, Takeuchi T, Shibue T, Takano H, Nishimura A, Fukuda Y, Singh SB. 2016. In vitro and in vivo characterization of the novel oxabicyclooctane-linked bacterial topoisomerase inhibitor AM-8722, a selective, potent inhibitor of bacterial DNA gyrase. Antimicrob Agents Chemother 60:4830–4839. doi: 10.1128/AAC.00619-16.

          Article
          PMC4958163 PMC4958163 4958163 00619-16
          10.1128/AAC.00619-16
          4958163
          27246784
          Copyright © 2016, American Society for Microbiology. All Rights Reserved.
          Page count
          Figures: 6, Tables: 5, Equations: 0, References: 30, Pages: 10, Words: 8962
          Funding
          This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
          Categories
          Experimental Therapeutics

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