Mechanism of inhibition of DNA gyrase by quinolone antibacterials: a cooperative drug--DNA binding model.
We have proposed a cooperative quinolone-DNA binding model for the inhibition of DNA gyrase. The essential feature of the model is that bound gyrase induces a specific quinolone binding site in the relaxed DNA substrate in the presence of ATP. The binding affinity and specificity are derived from two unique and equally important functional features: the specific conformation of the proposed single-stranded DNA pocket induced by the enzyme and the unique self-association phenomenon (from which the cooperativity is derived) of the drug molecules to fit the binding pocket with a high degree of flexibility. Supporting evidence for and implications of this model are provided.
Shen
L L
LL
Anti-Infective Research Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Mitscher
L A
LA
Sharma
P N
PN
O'Donnell
T J
TJ
Chu
D W
DW
Cooper
C S
CS
Rosen
T
T
Pernet
A G
AG
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D004269:DNA, Bacterial / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D009268:Nalidixic Acid / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D015363:Quinolones / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; D009268:Nalidixic Acid; D004247:DNA