Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV

Mitton‐Fry, Mark J.; Brickner, Steven J.; Hamel, Judith C.; Brennan, Lori; Casavant, Jeffrey; Chen, Michael; Chen, Tao; Ding, Xiaoyuan; Driscoll, James P.; Hardink, Joel R.; Hoang, Thuy; Hua, Erbing; Huband, Michael D.; Maloney, Meghan; Marfat, Anthony; McCurdy, Sandra P.; McLeod, Dale; Plotkin, Michael A.; Reilly, Usa; Robinson, Shaughn; Schafer, John R.; Shepard, Richard M.; Smith, James F.; Stone, Gregory G.; Subramanyam, Chakrapani; Yoon, Kwansik; Yuan, Wei; Zaniewski, Richard P.; Zook, Christopher

doi:10.1016/j.bmcl.2013.03.047

Cited by 54 publications

(67 citation statements)

References 40 publications

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“…In one study, for example, NBTI analogs displayed equipotent target affinity for Streptococcus pneumoniae gyrase and TopoIV but an asymmetrical profile toward the Staphylococcus aureus enzymes, with greater affinity for S. aureus gyrase (40). Another group concluded that an asymmetrical target profile in S. aureus led to unacceptably high resistance frequencies (3 ϫ 10 Ϫ6 at 4ϫ MIC) (41).…”

Section: Discussionmentioning

confidence: 99%

Target-Based Resistance in Pseudomonas aeruginosa and Escherichia coli to NBTI 5463, a Novel Bacterial Type II Topoisomerase Inhibitor

Nayar

Dougherty

Reck

et al. 2015

Antimicrob Agents Chemother

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), a novel bacterial type II topoisomerase inhibitor, NBTI 5463, with activity against Gram-negative pathogens was described. First-step resistance mutations in Pseudomonas aeruginosa arose exclusively in the nfxB gene, a regulator of the MexCD-OprJ efflux pump system. The present report describes further resistance studies with NBTI 5463 in both Pseudomonas aeruginosa and Escherichia coli. Second-step mutations in P. aeruginosa arose at aspartate 82 of the gyrase A subunit and led to 4-to 8-fold increases in the MIC over those seen in the parental strain with a first-step nfxB efflux mutation. A third-step mutant showed additional GyrA changes, with no changes in topoisomerase IV. Despite repeated efforts, resistance mutations could not be selected in E. coli. Genetic introduction of the Asp82 mutations observed in P. aeruginosa did not significantly increase the NBTI MIC in E. coli. However, with the aspartate 82 mutation present, it was possible to select second-step mutations in topoisomerase IV that did lead to MIC increases of 16-and 128-fold. As with the gyrase aspartate 82 mutation, the mutations in topoisomerase IV did not by themselves raise the NBTI MIC in E. coli. Only the presence of mutations in both targets of E. coli led to an increase in NBTI MIC values. This represents a demonstration of the value of balanced dual-target activity in mitigating resistance development.

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Section: Discussionmentioning

confidence: 99%

Target-Based Resistance in Pseudomonas aeruginosa and Escherichia coli to NBTI 5463, a Novel Bacterial Type II Topoisomerase Inhibitor

Nayar

Dougherty

Reck

et al. 2015

Antimicrob Agents Chemother

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“…ovel bacterial type II topoisomerase inhibitors (NBTIs) represent a new class of antimicrobial agents that display potent broad-spectrum antibacterial activity (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). NBTIs bind to and inhibit the essential bacterial enzymes DNA gyrase and topoisomerase IV at sites distinct from the fluoroquinolone-binding site; therefore, they retain activity against clinically relevant pathogens resistant to quinolones and other antibiotic agents.…”

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confidence: 99%

In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

Tan

Gill

Jin

et al. 2016

Antimicrob Agents Chemother

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dOxabicyclooctane-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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“…The ketone was protected as its cyclic acetal (10), and the ester moieties were then reduced with LiAlH 4 to furnish the diol (11) that was subsequently converted to bis tosylate (12). The ketone group of the tosylate was unmasked by reaction with diluted HCl to give 13, which was reacted with vinylmagnesium bromide to provide alcohol 14.…”

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confidence: 99%

Oxabicyclooctane-Linked Novel Bacterial Topoisomerase Inhibitors as Broad Spectrum Antibacterial Agents

Singh

Kaelin

Jin

et al. 2014

ACS Med. Chem. Lett.

106

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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 IC 50 > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC 50 = 1.02 μM) and topo IV (IC 50 = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED 50 ) 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.

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Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV

Cited by 54 publications

References 40 publications

Target-Based Resistance in Pseudomonas aeruginosa and Escherichia coli to NBTI 5463, a Novel Bacterial Type II Topoisomerase Inhibitor

Target-Based Resistance in Pseudomonas aeruginosa and Escherichia coli to NBTI 5463, a Novel Bacterial Type II Topoisomerase Inhibitor

In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

Oxabicyclooctane-Linked Novel Bacterial Topoisomerase Inhibitors as Broad Spectrum Antibacterial Agents

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