Staphylococcus aureus, with confirmed selectivity over the human topoisomerase IIα enzyme.Singh, Sheo B.; Kaelin, David E.; Wu, Jin; Miesel, Lynn; Tan, Christopher M.; Meinke, Peter T.; Olsen, David B.; Lagrutta, Armando; Wei, Changqing; Liao, Yonggang; Peng, Xuanjia; Wang, Xiu; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Yajima, Masanobu; Shibue, Taku; Shibata, Takeshi; Ohata, Kohei; Nishimura, Akinori; Fukuda, YasumichiOxabicyclooctane linked 1,5-naphthyridinyl-pyridoxazinones are novel broad-spectrum bacterial topoisomerase inhibitors (NBTIs) targeting bacterial DNA gyrase and topoisomerase IV at a site different than quinolones.

A recent review covered the state-of-the-art optimization efforts that have been invested in hERG improvements.The antibacterial activities of the NBTIs have never been disputed, although further improvements appear to be necessary, particularly because of the NBTI-induced cardiotoxicity issues. was advanced into phase I clin. Results: Described here is the synthesis and biol. studies.Singh, Sheo B.; Kaelin, David E.; Wu, Jin; Miesel, Lynn; Tan, Christopher M.; Black, Todd; Nargund, Ravi; Meinke, Peter T.; Olsen, David B.; Lagrutta, Armando; Lu, Jun; Patel, Sangita; Rickert, Keith W.; Smith, Robert F.; Soisson, Stephen; Sherer, Edward; Joyce, Leo A.; Wei, Changqing; Peng, Xuanjia; Wang, Xiu; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Takano, Hisashi; Shibasaki, Mitsuhito; Yajima, Masanobu; Nishimura, Akinori; Shibata, Takeshi; Fukuda, YasumichiNovel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. We report our research efforts aimed at expanding the antibacterial spectrum of this class of mols. organisms via inhibition of type II bacterial topoisomerases was discovered. studies.There is no corresponding record for this reference.Black, Michael T.; Stachyra, Therese; Platel, Denis; Girard, Anne-Marie; Claudon, Monique; Bruneau, Jean-Michel; Miossec, ChristineNXL101 is one of a new class of quinoline antibacterial DNA gyrase and topoisomerase IV inhibitors showing potent activity against gram-pos. to accumulate in Escherichia coli. starting points for medicinal chemists.There is no corresponding record for this reference.Miles, Timothy J.; Barfoot, Christopher; Brooks, Gerald; Brown, Pamela; Chen, Dongzhao; Dabbs, Steven; Davies, David T.; Downie, David L.; Eyrisch, Susanne; Giordano, Ilaria; Gwynn, Michael N.; Hennessy, Alan; Hoover, Jennifer; Huang, Jianzhong; Jones, Graham; Markwell, Roger; Rittenhouse, Stephen; Xiang, Hong; Pearson, NeilAs part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compds. Here the authors assess the ability of over 180 diverse compds. 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.

were evaluated against a panel of key Gram-pos. relevant resistance phenotypes. suggested that a protein dimer with two symmetry-related SD8s was more likely. These structures have the DNA in various cleavage states and appear to track trajectories along the catalytic paths of the DNA cleavage/religation steps. (A) Substitution patterns of the most common NBTI linker fragments. potency. showed potent antibacterial activity, but also showed potent hERG binding activity. The structure-activity relationships of this series, with an emphasis on the length and conformation of the linker was also investigated. The merits of the most prominent novel antibiotics that have reached, or are expected to reach the clin. During the course of the optimization program, lead compd. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. A comparison of the two structures demonstrates conformational flexibility within the central linker of gepotidacin, which may contribute to the activity of the compd.Bax, Benjamin D.; Murshudov, Garib; Maxwell, Anthony; Germe, ThomasType II topoisomerases regulate DNA topol. and oral efficacy (ED50) at 3.2 and 27 mg/kg doses, resp., in a murine model of bacteremia. Chem.280, 14 252-14 263, doi:10.1074/jbc.M500156200). X-ray crystallog. cure was achieved in 66/69 (96%) urogenital infections. The amides showed highly improved hERG (functional IC50 >30 μM) profile.Biedenbach, D. J.; Bouchillon, S. K.; Hackel, M.; Miller, L. A.; Scangarella-Oman, N. E.; Jakielaszek, C.; Sahm, D. F.Gepotidacin inhibits bacterial DNA replication through a mode different from that of fluoroquinolones. pathogens. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. Bicyclic heterocycles appeared to be the best RHS moiety for the hydroxy-tricyclic oxabicyclooctane linked NBTIs.There is no corresponding record for this reference.There is no corresponding record for this reference.Li, Linsen; Okumu, Antony; Dellos-Nolan, Sheri; Li, Zoe; Karmahapatra, Soumendrakrishna; English, Anthony; Yalowich, Jack C.; Wozniak, Daniel J.; Mitton-Fry, Mark J.Novel bacterial type II topoisomerase inhibitors (NBTIs) constitute a promising new class of antibacterial agents. This work describes the structures of a further truncated form of the GyrA N-terminal domain fragment (GyrA55) with and without SD8 bound. Unlike fluoroquinolones, which induce primarily double-stranded DNA breaks, gepotidacin induced high levels of gyrase-mediated single-stranded breaks. The gepotidacin MIC90s were as follows (in micrograms per mL) for the indicated bacteria: Streptococcus pyogenes, 0.25; Escherichia coli, 2; Moraxella catarrhalis, ≤0.06; Streptococcus pneumoniae (0.25), Haemophilus influenzae, 1; Clostridium perfringens, 0.5; and Shigella spp., 1, including levofloxacin-resistant subsets.


0�-7�T Due to lack of cross-resistance to known antibiotics they present excellent opportunity to combat drug-resistant bacteria.

without permission from the American Chemical Society. were evaluated for efficacy in a murine bacteremia model of Staphylococcus aureus infection.

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