Exploiting bacterial DNA gyrase as a drug target: current state and perspectives.
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TLDR
Known gyrase-specific drugs and toxins are reviewed and the prospects for developing new antibacterials targeted to this enzyme are assessed.Abstract:
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.read more
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References
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Journal ArticleDOI
The intrinsic ATPase of DNA gyrase.
A Sugino,N R Cozzarelli +1 more
TL;DR: It is concluded that gyrase contains an intrinsic, DNA-dependent, ATPase, which is relatively insensitive to oxolinic acid, a good inhibitor of supercoiling, whereas novobiocin inhibits both processes equally.
Book ChapterDOI
Mechanisms of quinolone resistance
TL;DR: In this paper, the authors summarized the current understanding of established mechanisms of resistance to this class of antimicrobial agents in gram-positive bacteria and suggested the involvement of an efflux system(s) in quinolone resistance.
Journal ArticleDOI
Mutations in DNA gyrase result in novobiocin resistance in halophilic archaebacteria.
TL;DR: A cloning vector for use in halophilic archaebacteria which has a novobiocin resistance determinant as a selectable marker is developed and three mutations were identified in the GyrB protein of the resistant mutant compared with the wild type which together enable Haloferax cells to grow in concentrations of novobocin some 1,000 times higher than that possible for cells carrying only the wild-type enzyme.
Journal ArticleDOI
Structural insights into the quinolone resistance mechanism of Mycobacterium tuberculosis DNA gyrase.
Jérémie Piton,Jérémie Piton,Stéphanie Petrella,Marc Delarue,Marc Delarue,Gwenaëlle André-Leroux,Gwenaëlle André-Leroux,Vincent Jarlier,Alexandra Aubry,Claudine Mayer,Claudine Mayer,Claudine Mayer +11 more
TL;DR: Interestingly, the structure of the entire breakage-reunion domain revealed a new interaction, in which the Quinolone-Binding Pocket (QBP) is blocked by the N-terminal helix of a symmetry-related molecule, which provides useful starting points for designing peptide based inhibitors that target DNA gyrase to prevent its binding to DNA.
Journal ArticleDOI
Mechanism of action of the antibiotic NXL101, a novel nonfluoroquinolone inhibitor of bacterial type II topoisomerases.
Michael T. Black,Thérèse Stachyra,Denis Platel,Anne-Marie Girard,Monique Claudon,Jean-Michel Bruneau,Christine Miossec +6 more
TL;DR: NXL101 inhibited topoisomerase IV more effectively than gyrase from Escherichia coli, whereas the converse is true of enzymes from Staphylococcus aureus, indicating apparent target preference is opposite to that which is associated with most fluoroquinolone antibiotics.
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