Mechanism of Inhibition of DNA Gyrase by ES‐1273, a Novel DNA Gyrase Inhibitor

Abstract

, replication, chromosome condensation and segregation (2). DNA gyrase and topo IV share significant sequence similarity and have essentially the same ATP-dependent catalytic mechanism. They alter the topological state of DNA by producing a transient double-stranded break in one duplex (G-segment, the gate-forming segment), transporting another duplex (T-segment, the transported segment) through the enzyme-mediated gate, and religating the cleaved G-segment. This reaction can achieve all the known reactions of DNA gyrase and topo IV: relaxation and supercoiling, catenation and decatenation, and knotting and unknotting. DNA gyrase is unique in catalyzing the negative supercoiling of closed circular DNA. The supercoiling capability is considered to act ahead of replication forks promoting fork progression by removing the positive supercoils that arise during DNA unwinding (9, 29). In contrast, topo IV relaxes positive and negative supercoils, and is normally localized behind the replication forks to serve as decatenating enzyme for disentangling the interlinked daughter chromosomes (9, 29). DNA gyrase and topo IV consist of an A 2 B 2 heterotetramer encoded by the gyrA and gyrB, and a C 2 E 2 heterotetramer encoded by the parC and parE, respectively. The GyrA and ParC comprise an N-terminal domain involved in DNA cleavage and religation and a C-terminal DNA-wrapping domain. The

Identification and Characterization of Topoisomerase II Inhibitory Peptides from Soy Protein Hydrolysates

“…GIH inhibited 50% of topoisomerase I activity at 2.45 mg/mL and 61% of topoisomerase II activity at 0.5 mg/mL, indicating that GIH is more potent as a human topoisomerase II inhibitor than a topoisomerase I inhibitor (Figures and ). This topoisomerase specific inhibition, which is not uncommon, has previously been observed for a DNA gyrase inhibitor obtained by optimization of a pyrazole derivative; this compound inhibits human topoisomerase II but not topoisomerase I . These results prompted us to focus further analysis on topoisomerase II inhibitory peptides.…”

Non-quinolone Inhibitors of Bacterial Type IIA Topoisomerases: A Feat of Bioisosterism

“…If this compound could conceivably be an inhibitor of the ATPase function of DNA gyrase, a medicinal chemistry program led to far more efficient N-aryl analogues such as ES-1273 ( 101 ). − As this N-aryl ring component could not possibly fit in models of the ATP-binding pocket, further work proved that such compounds are indeed inhibiting bacterial DNA gyrase and topoisomerase IV by another, unidentified mechanism. Moreover, compound 101 was also found to be active on human topoisomerase IIα but not on topoisomerase I …”

Characterization of Campylobacter jejuni DNA gyrase as the target of quinolones

“…In bacteria, the target of quinolones are the essential enzymes DNA gyrase and DNA topoisomerase IV, belonging to the bacterial type II topoisomerase. DNA gyrase is unique in that it catalyzes the negative supercoiling of DNA and is essential for DNA replication, transcription and recombination [8]. On the contrary, topoisomerase IV has a specialized role in chromosome segregation.…”