title: Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad spectrum antibacterial agents.
abstract: Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC50 > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC50 = 1.02 μM) and topo IV (IC50 = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED50) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker.
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Kaelin
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: Miesel
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Tan
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: David
authors.initials: D
authors.lastname: Olsen
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Armando
authors.initials: A
authors.lastname: Lagrutta
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Prudence
authors.initials: P
authors.lastname: Bradley
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Sangita
authors.initials: S
authors.lastname: Patel
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Rickert
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Smith
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Soisson
authors.affiliation: WuXi AppTec , Shanghai, People's Republic of China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Wei
authors.affiliation: Kyorin Pharmaceutical Co., Ltd. , 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Fukuda
authors.affiliation: Kyorin Pharmaceutical Co., Ltd. , 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kishii
authors.affiliation: Kyorin Pharmaceutical Co., Ltd. , 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takei
authors.affiliation: Kyorin Pharmaceutical Co., Ltd. , 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Fukuda
keywords: Antibacterial; NBTI; broad spectrum; gyrase inhibitors; novel bacterial topoisomerase inhibitors; oxabicyclooctane; topoisomerase IV inhibitors