期刊
MOLECULES
卷 26, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/molecules26051234
关键词
gyrase; mechanism; inhibition; single-molecule FRET; conformational changes
资金
- Deutsche Forschungsgemeinschaft [KL1153/5-1, KL1153/9-1, KL1153/9-2]
Gyrase is an essential bacterial type IIA topoisomerase that catalyzes negative supercoiling of DNA. Current inhibitors of gyrase often have severe side effects and lose antibiotic activity due to resistance mutations, highlighting the need for novel and improved inhibitors.
Gyrase is a bacterial type IIA topoisomerase that catalyzes negative supercoiling of DNA. The enzyme is essential in bacteria and is a validated drug target in the treatment of bacterial infections. Inhibition of gyrase activity is achieved by competitive inhibitors that interfere with ATP- or DNA-binding, or by gyrase poisons that stabilize cleavage complexes of gyrase covalently bound to the DNA, leading to double-strand breaks and cell death. Many of the current inhibitors suffer from severe side effects, while others rapidly lose their antibiotic activity due to resistance mutations, generating an unmet medical need for novel, improved gyrase inhibitors. DNA supercoiling by gyrase is associated with a series of nucleotide- and DNA-induced conformational changes, yet the full potential of interfering with these conformational changes as a strategy to identify novel, improved gyrase inhibitors has not been explored so far. This review highlights recent insights into the mechanism of DNA supercoiling by gyrase and illustrates the implications for the identification and development of conformation-sensitive and allosteric inhibitors.
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