title: In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase.
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.
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA christopher_tan@merck.com sheo.singh.215@gmail.com.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Tan
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Gill
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Toussaint
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey, USA.
authors.forename: Jingjun
authors.initials: J
authors.lastname: Yin
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsuchiya
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Garlisi
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kaelin
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Miesel
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Armando
authors.initials: A
authors.lastname: Lagrutta
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Fukuda
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kishii
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takei
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Oohata
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Shibue
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Takano
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishimura
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA christopher_tan@merck.com sheo.singh.215@gmail.com.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D034242:Cyclooctanes / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism*; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004269:DNA, Bacterial / Q000235:genetics; D004285:Dogs; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D004927:Escherichia coli Infections / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D051381:Rats; D017208:Rats, Wistar; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D034242:Cyclooctanes; D004269:DNA, Bacterial; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II; C474479:cyclooctane