Discovery and development of ATPase inhibitors of DNA gyrase as antibacterial agents.
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.
Oblak
Marko
M
Lek Pharmaceuticals, D.D., Drug Discovery, Ljubljana, Slovenia. marko.oblak@sandoz.com
Kotnik
Miha
M
Solmajer
Tom
T
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D001665:Binding Sites; D003374:Coumarins / Q000494:pharmacology; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D015195:Drug Design; D010456:Peptides, Cyclic / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D014227:Triazines / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001393:Azoles; D001562:Benzimidazoles; D003374:Coumarins; D010456:Peptides, Cyclic; D011743:Pyrimidines; D059005:Topoisomerase II Inhibitors; D014227:Triazines; C085889:cyclothialidine; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase