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

Kern, Günther; Palmer, Tiffany; Ehmann, David E.; Shapiro, Adam B.; Andrews, Beth; Basarab, Gregory S.; Doig, P.; Fan, Jun; Gao, Ning; Mills, Scott D.; Mueller, John P.; Sriram, Shubha; Thresher, Jason; Walkup, Grant K.

doi:10.1074/jbc.m115.663534

Cited by 42 publications

(104 citation statements)

References 48 publications

(52 reference 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%

Antibiotics in the clinical pipeline at the end of 2015

2016

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There is growing global recognition that the continued emergence of multidrug-resistant bacteria poses a serious threat to human health. Action plans released by the World Health Organization and governments of the UK and USA in particular recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics. This review lists the 30 antibiotics and two β-lactamase/β-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new β-lactam/β-lactamase inhibitor combinations launched since 2013. The development status, mode of action, spectra of activity and genesis (natural product, natural product-derived, synthetic or protein/mammalian peptide) of the 37 compounds and six β-lactamase/β-lactam combinations being evaluated in clinical trials between 2013 and 2015 are discussed. Compounds discontinued from clinical development since 2013 and new antibacterial pharmacophores are also reviewed.

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Section: Compounds Undergoing Clinical Evaluationmentioning

confidence: 99%

Antibiotics in the clinical pipeline at the end of 2015

2016

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“…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%

Targeting Bacterial Topoisomerases: How to Counter Mechanisms of Resistance

Tse‐Dinh

2016

Future Med. Chem.

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DNA gyrase and topoisomerase IV are type IIA bacterial topoisomerases that are targeted by highly effective antibiotics. However, resistance via multiple mechanisms arises to limit the efficacies of these drugs. Continued research on type IIA bacterial topoisomerases has provided novel approaches to counter the most common resistance mechanism for utilization of these proven targets in antibacterial therapy. Bacterial topoisomerase I is being explored as an alternative target that is not expected to show cross-resistance. Dual targeting or combination therapy could be strategies for circumventing the development of resistance to topoisomerase-targeting antibiotics. Bacterial topoisomerases are high-value bactericidal targets that could continue to be exploited for antibacterial therapy, if new tactics to counter resistance can be adopted.

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“…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%

In vitro growth of multidrug-resistant Neisseria gonorrhoeae isolates is inhibited by ETX0914, a novel spiropyrimidinetrione

Papp

Lawrence

Sharpe

et al. 2016

International Journal of Antimicrobial Agents

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Antimicrobial resistance in Neisseria gonorrhoeae has severely limited the number of treatment options, and the emergence of extended-spectrum cephalosporin resistance threatens the effectiveness of the last remaining recommended treatment regimen. This study assessed the in vitro susceptibility of N. gonorrhoeae to ETX0914, a novel spiropyrimidinetrione that inhibits DNA biosynthesis. In vitro activity was determined by agar dilution against 100 N. gonorrhoeae isolates collected from men presenting with urethritis in the USA during 2012–2013 through the Gonococcal Isolate Surveillance Project. The minimum inhibitory concentration (MIC) that inhibited growth in 50% (MIC50) and 90% (MIC90) of isolates was calculated for each antimicrobial agent. ETX0914 demonstrated a high level of antimicrobial activity against N. gonorrhoeae, including isolates with decreased susceptibility or resistance to currently available agents. The ability of ETX0914 to inhibit the growth of N. gonorrhoeae was similar to ceftriaxone, which is currently recommended in combination with azithromycin to treat gonorrhoea. The data presented in this study strongly suggest that ETX0914 should be evaluated in a clinical trial for the treatment of N. gonorrhoeae.

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

Cited by 42 publications

References 48 publications

Antibiotics in the clinical pipeline at the end of 2015

Antibiotics in the clinical pipeline at the end of 2015

Targeting Bacterial Topoisomerases: How to Counter Mechanisms of Resistance

In vitro growth of multidrug-resistant Neisseria gonorrhoeae isolates is inhibited by ETX0914, a novel spiropyrimidinetrione

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