Mode of action of GR122222X, a novel inhibitor of bacterial DNA gyrase

Oram, Mark; Dosanjh, Bhupinder; Gormley, Niall; Smith, Clare V.; Fisher, L.M.; Maxwell, Anthony; Duncan, Ken

doi:10.1128/aac.40.2.473

Cited by 26 publications

(13 citation statements)

References 28 publications

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“…Cyclothialidine (Ro 09-1437; Fig. 4 ) is produced by Streptomyces filipinensis and has been shown to target DNA gyrase specifically by binding to the B subunit and inhibiting the ATPase activity (Goetschi et al 1993 ; Nakada et al 1994 ; Oram et al 1996 ). A crystal structure of the related compound GR122222X shows that, like novobiocin, the compound binds to the GyrB N-terminal domain at a site that overlaps with the ATP-binding site (Lewis et al 1996a ).…”

Section: Other Small Molecule Inhibitorsmentioning

confidence: 99%

Exploiting bacterial DNA gyrase as a drug target: current state and perspectives

Collin

Karkare

Maxwell

2011

Appl Microbiol Biotechnol

482

375

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DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme.

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Section: Other Small Molecule Inhibitorsmentioning

confidence: 99%

Exploiting bacterial DNA gyrase as a drug target: current state and perspectives

Collin

Karkare

Maxwell

2011

Appl Microbiol Biotechnol

482

375

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“…The specificity of cyclothialidines for gyrase over type II topoisomerases is presumably conferred by subtle differences between the structures of gyrase and topoisomerase II at the periphery of the ATP-binding site. However, the major problem for the use of cyclothialidines as antibiotics is that their antibacterial potency is much reduced in comparison to their DNA gyrase inhibitory char-d i ne (63,66). a Review art ides acteristic.…”

Section: Structure Of the P24/cyclothialidine Complexmentioning

confidence: 99%

Molecular mechanisms of durg inhibition of DNA gyrase

1996

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SummaryDNA gyrase, an enzyme unique to prokaryotes, has been implicated in almost all processes that involve DNA. Although efficient inhibitors of this protein have been known for more than 20 years, none of them have enjoyed prolonged pharmaceutical success. It is only recently that the mechanisms of inhibition for some of these classes of drugs have been established unequivocally by X-ray crystallography. It is hoped that this detailed structural information will assist the Accepted design of novel, effective inhibitors of DNA gyrase.

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“…The inhibition mechanism of cyclothialidine was characterized by competition experiments with radiolabelled benzoylcyclothialidine [60] and dihydronovobiocin [61]. Similarly to coumarins, cyclothialidine and its close analog GR122222X (N-terminal alanine instead of serine) inhibit the ATPase activity of DNA gyrase and both bind to the N-terminal 43 kDa fragment of GyrB in a stoichiometric ratio of 1:1 [60,61].…”

Section: Cyclothialidinesmentioning

confidence: 99%

Discovery and Development of ATPase Inhibitors of DNA Gyrase as Antibacterial Agents

Oblak¹,

Kotnik²,

Šolmajer³

2007

CMC

116

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DNA gyrase is an attractive and well established target for the development of antibacterial agents. This bacterial enzyme, whose biological function is to control the topological state of DNA molecules, consists of two catalytic subunits; GyrA is responsible for DNA breakage and reunion, while the subunit GyrB contains the ATP-binding site. Coumarins and cyclothialidines are natural products that inhibit the ATPase activity of DNA gyrase by blocking the binding of ATP to subunit GyrB. The mechanism of action of these compounds was exhaustively characterized by biochemical methods and supported by protein crystallography. The abundance of crystallographic data on the N-terminal domain of GyrB in its complexes with various ligands has enabled the structure-based design of novel efficient chemotypes as inhibitors of the ATPase domain. This review summarizes the discovery of ATPase inhibitors of DNA gyrase B in the last decade and their development as potential antibacterial agents.

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Mode of action of GR122222X, a novel inhibitor of bacterial DNA gyrase

Cited by 26 publications

References 28 publications

Exploiting bacterial DNA gyrase as a drug target: current state and perspectives

Exploiting bacterial DNA gyrase as a drug target: current state and perspectives

Molecular mechanisms of durg inhibition of DNA gyrase

Discovery and Development of ATPase Inhibitors of DNA Gyrase as Antibacterial Agents

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