2015
DOI: 10.1074/jbc.m115.663534
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Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914

Abstract: 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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Cited by 43 publications
(104 citation statements)
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“…229 ETX0914 (38) is a novel spiropyrimidinetrione that targets bacterial topoisomerase II with a mode of inhibition distinct from the fluoroquinolones and aminocoumarins, meaning it retains activity against fluoroquinolone resistant isolates. 230,231 Debio-1452 (39) (AFN 1250) was being developed by Affinium Pharmaceuticals (Austin, TX, USA) and successfully completed a phase-IIa trial in August 2012 (NCT01519492) as an oral formulation for the treatment of staphylococcal ABSSSI. Debio-1452 (39) disrupts fatty acid biosynthesis by inhibiting staphylococcal FabI, 232,233 an essential enzyme in the final step of the fatty acid elongation cycle, 234,235 and was derived from a benzodiazepine identified at GSK (London, UK) using a high-throughput screen looking for inhibitors of S. aureus FabI.…”
Section: Compounds Undergoing Clinical Evaluationmentioning
confidence: 99%
“…229 ETX0914 (38) is a novel spiropyrimidinetrione that targets bacterial topoisomerase II with a mode of inhibition distinct from the fluoroquinolones and aminocoumarins, meaning it retains activity against fluoroquinolone resistant isolates. 230,231 Debio-1452 (39) (AFN 1250) was being developed by Affinium Pharmaceuticals (Austin, TX, USA) and successfully completed a phase-IIa trial in August 2012 (NCT01519492) as an oral formulation for the treatment of staphylococcal ABSSSI. Debio-1452 (39) disrupts fatty acid biosynthesis by inhibiting staphylococcal FabI, 232,233 an essential enzyme in the final step of the fatty acid elongation cycle, 234,235 and was derived from a benzodiazepine identified at GSK (London, UK) using a high-throughput screen looking for inhibitors of S. aureus FabI.…”
Section: Compounds Undergoing Clinical Evaluationmentioning
confidence: 99%
“…AZD0914 has potent activity against Gram-positive, fastidious Gram-negative and atypical bacteria [39]. It showed selectivity of acting as a topoisomerase poison inhibitor for Neisseria gonorrhoeae gyrase and topoisomerase IV over human topoisomerase IIα and IIβ [38]. With low spontaneous resistance frequency (1.5 × 10 -8 to <5.2 × 10 -9 at 4 × the MIC) and lack of cross-resistance to pre-existing fluoroquinolone and cephalosporin resistance mechanisms in N. gonorrhoeae [71], AZD0914 is being tested in clinical trials (ClinicalTrials website) to help meet the challenge of untreatable gonorrhea [72].…”
Section: New Inhibitors Interacting Near the Active Site Of Gyrase Thmentioning
confidence: 99%
“…The compound stabilises the cleaved covalent of DNA gyrase and prevents religation of DNA bound to the topoisomerase tetramer [12]. Although ETX0914 and ciprofloxacin both target DNA gyrase, the distinct binding modes are functionally sufficient for ETX0914 to inhibit the growth of ciprofloxacin-resistant strains [11,13]. …”
Section: Introductionmentioning
confidence: 99%