Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization

Basarab, Gregory S.; Brassil, Patrick; Doig, P.; Galullo, Vincent; Haimes, Howard B.; Kern, Günther; Kutschke, Amy; McNulty, John; Schuck, Virna; Stone, Gregory G.; Gowravaram, Madhusudhan

doi:10.1021/jm501174m

Cited by 47 publications

(59 citation statements)

References 44 publications

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“…Strains exist with efflux pumps knocked out either individually or in combination, and the relative contribution of each system to the susceptibility to major classes of antimicrobials has been defined (15). For the most part, tolC is the major contributor to efflux in E. coli, and knockout of this gene is often used to assess whether novel compounds lack cellular activity due to efflux (16)(17)(18)(19)(20)(21)(22)(23)(24). Similarly, mutations in several genesincluding lpxC (25-27), lptD (28, 29), and lptE (30, 31)-leading to increased permeability of E. coli have been described, and strains harboring such lesions are often used to assess the effect of increased cellular penetration on the bioactivity of molecules (32-37).…”

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confidence: 99%

Mutant Alleles of lptD Increase the Permeability of Pseudomonas aeruginosa and Define Determinants of Intrinsic Resistance to Antibiotics

Balibar

Grabowicz

2016

Antimicrob Agents Chemother

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bGram-negative bacteria provide a particular challenge to antibacterial drug discovery due to their cell envelope structure. Compound entry is impeded by the lipopolysaccharide (LPS) of the outer membrane (OM), and those molecules that overcome this barrier are often expelled by multidrug efflux pumps. Understanding how efflux and permeability affect the ability of a compound to reach its target is paramount to translating in vitro biochemical potency to cellular bioactivity. Herein, a suite of Pseudomonas aeruginosa strains were constructed in either a wild-type or efflux-null background in which mutations were engineered in LptD, the final protein involved in LPS transport to the OM. These mutants were demonstrated to be defective in LPS transport, resulting in compromised barrier function. Using isogenic strain sets harboring these newly created alleles, we were able to define the contributions of permeability and efflux to the intrinsic resistance of P. aeruginosa to a variety of antibiotics. These strains will be useful in the design and optimization of future antibiotics against Gram-negative pathogens. With emerging multidrug resistance and a limited number of treatment options, bacterial infections pose an ever growing threat to human health. Gram-negative bacteria are particularly recalcitrant to antimicrobial intervention due to their cell envelope structure. Possessing two membranes with different chemical properties (1) and containing an arsenal of efflux pumps (2), Gram-negative bacteria are capable of both excluding and expelling molecules, rendering them resistant to many drugs. Despite major Gram-negative pathogens being classified as urgent or serious threats by the CDC (3), no Gram-negative-active antibiotic with a new mechanism of action has been introduced in over 40 years. Of the 28 new antibiotics approved since 2000, only 18 are indicated for treatment of Gram-negative bacteria (4), and all of those are derived from the four legacy classes ␤-lactams, tetracyclines, macrolides, and fluoroquinolones, which were first introduced in 1942 (5), 1948 (6), 1952 (7), and 1967 (8), respectively. Novel derivatives of old antibiotics often have limited spectra of coverage and can only do so much to overcome existing mechanisms of resistance; therefore, introduction of novel classes of antibiotics is critical.There is no shortage of potential targets in the antibacterial space given that the essential gene set for several Gram-negative pathogens has been defined (9-12). However, despite genetically demonstrating target essentiality, cognate inhibitors with exquisite in vitro activity often have no measurable cellular activity (13,14). The reasons for this can be attributed to a lack of penetration of compounds into bacteria, efflux of molecules out of bacteria, insufficient inhibition of the target, metabolism within the cells, or a combination of the aforementioned factors. Understanding the reason for failure to translate enzymatic 50% inhibitory concentrations (IC 50 s) into cellular MICs is paramou...

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confidence: 99%

Mutant Alleles of lptD Increase the Permeability of Pseudomonas aeruginosa and Define Determinants of Intrinsic Resistance to Antibiotics

Balibar

Grabowicz

2016

Antimicrob Agents Chemother

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“…Thus, it is expected that AZD0914 should not exhibit significant mechanism-based toxicity in humans. Indeed, AZD0914 showed no in vitro mammalian genotoxicity and no measurable toxicity in an in vivo rat micronucleus assay (21).…”

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confidence: 99%

Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914

Kern

Palmer

Ehmann

et al. 2015

Journal of Biological Chemistry

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Background: Inhibition of Neisseria gonorrhoeae type II topoisomerases gyrase and TopoIV by the antibacterial spiropyrimidinetrione AZD0914 was investigated. Results: AZD0914 stabilized the gyrase-DNA complex with double strand DNA cleavage, retaining potency in a fluoroquinolone-resistant mutant, with little inhibition of human type II topoisomerases. Conclusion: AZD0914 displays mechanistic differences from fluoroquinolones. Significance: AZD0914 has the potential to combat drug-resistant gonorrhea.

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“…Interestingly, several potent inhibitors such as novobiocin, clorobiocin, cyclothialidine, and 5ʹ-adenylyl-β,γ-imidodiphosphate (ATP analog) were found to interact with Asp-73, crucial amino acid present in the ATP binding domain of DNA Gyrase [32]. Basarab et al synthesized spiropyrimidinetriones with a benzisoxazole heterocyclic scaffold and reported that these derivatives possess potent DNA Gyrase inhibitory activity [33]. Literature findings revealed that various oxazolones derivatives exhibit potent antimicrobial activity against Gramnegative and Gram-positive organisms.…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

Synthesis, in Silico Studies and Evaluation of Antibacterial Activity of 4-Substituted Benzylidene-2-(Phenoxymethyl) Oxazol-5(4h)-Ones

Begum¹,

Sk²,

Maneesha³

et al. 2019

Asian J Pharm Clin Res

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Objective: Arylidene-1, 3-oxazol-5-ones represent potential antibacterial agents. In the present work, a series of 4-substituted benzylidene-2- (phenoxymethyl) oxazol-5(4H)-ones were synthesized and screened for antibacterial activity against Gram-negative bacteria Escherichia coli. To explore plausible mechanisms, synthesized compounds were docked with DNA-Gyrase enzyme. Methods: All the reactants, phenoxy acetyl chloride, acetic anhydride, sodium acetate, substituted aromatic aldehydes, and glycine were triturated in a mortar by mechanical stirring. The antibacterial potentiality of the compounds was screened against E. coli using the disk diffusion method and the activity was recorded as a zone of inhibition. Results: Compound 2d, possessing 3, 4, 5-trimethoxy functionality on benzylidene ring exhibited the highest activity with 19 mm of the zone of inhibition which might be due to its higher interactions with DNA-Gyrase enzyme (ΔG-8.41 kcal/mol). Compounds 2a, 2b, and 2c exhibited moderate activity in the antimicrobial assay as well as in docking study indicating the positive contribution of substitution on benzylidene ring. Conclusion: A series of 4-substituted benzylidene-2-(phenoxymethyl) oxazol-5(4H)-ones were synthesized and evaluated for antibacterial activity. Compounds 2a, 2b, and 2c displayed moderate activity whereas 2d showed maximum zone of inhibition (19 mm). The good activity of these derivatives presumed to be due to the conformational flexibility of phenoxy methylene moiety which can be well accommodated in the target binding site.

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Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization

Cited by 47 publications

References 44 publications

Mutant Alleles of lptD Increase the Permeability of Pseudomonas aeruginosa and Define Determinants of Intrinsic Resistance to Antibiotics

Mutant Alleles of lptD Increase the Permeability of Pseudomonas aeruginosa and Define Determinants of Intrinsic Resistance to Antibiotics

Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914

Synthesis, in Silico Studies and Evaluation of Antibacterial Activity of 4-Substituted Benzylidene-2-(Phenoxymethyl) Oxazol-5(4h)-Ones

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