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Antimicrobial Agents and Chemotherapy, May 1998, p. 1022-1027, Vol. 42, No. 5
Department of Pharmacology, University of
Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical
School, Piscataway, New Jersey 08854
Received 11 September 1997/Returned for modification 5 January
1998/Accepted 5 February 1998
An uncoupler of oxidative phosphorylation, 2,4-dinitrophenol, and
an aconitase inhibitor, fluoroacetic acid, both of which are known to
lower the cellular ATP pool, protected Escherichia coli
cells from the bactericidal actions of gyrase poisons including quinolone antibiotics, nalidixic acid and ciprofloxacin, and the epipodophyllotoxins VP-16 and VM-26. Using purified E. coli
DNA gyrase, we examined the effect of ATP on gyrase-mediated DNA
cleavage in the presence of these gyrase poisons. ATP was shown to
stimulate gyrase-mediated DNA cleavage from 10- to more than 100-fold
in the presence of these gyrase poisons. ADP antagonized the
stimulatory effect of ATP. Consequently, gyrase-mediated DNA cleavage
induced by gyrase poisons is modulated by the ATP concentration/ADP
concentration ([ATP]/[ADP]) ratio. Coumermycin A1, an inhibitor of
the ATPase subunit of DNA gyrase, like ADP, also effectively
antagonized the stimulatory effect of ATP on gyrase-mediated DNA
cleavage induced by gyrase poisons. Furthermore, coumermycin A1, like
DNP and fluoroacetic acid, also protected cells from the bactericidal action of gyrase poisons. In the aggregate, our results are consistent with the notion that the [ATP]/[ADP] ratio, through its modulatory effect on the gyrase-mediated DNA cleavage, is an important determinant of cellular susceptibility to gyrase poisons.
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Copyright © 1998, American Society for Microbiology. All rights reserved.
Modulation of Gyrase-Mediated DNA Cleavage and
Cell Killing by ATP
*
Corresponding author. Mailing address: Department of
Pharmacology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Ln., Piscataway, NJ 08854. Phone: (908) 235-4592. Fax: (908) 235-4073. E-mail: lliu{at}umdnj.edu.
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