Association between early inhibiton of DNA synthesis and the MICs and MBCs of carboxyquinolone antimicrobial agents for wild-type and mutant [gyrA nfxB(ompF) acrA] Escherichia coli K-12

R. T. Chow, T. J. Dougherty, H. S. Fraimow, Eran Y. Bellin, M. H. Miller

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Abstract

Quinolone antimicrobial agents are known to interact with DNA gyrase, but the mechanism by which bacterial cell death occurs is not fully understood. In order to determine whether there is a correlation between quinolone-induced inhibition of early (i.e., 10 to 15 min) DNA synthesis and potency (MICs and MBCs), we measured the rate of DNA synthesis in log-phase Escherichia coli K-12 by using [3H]thymidine incorporation. Three quinolones (ciprofloxacin, norfloxacin, and difloxacin) were selected based on their decreasing activity against reference strain KL16. All three quinolones caused an early 50% inhibition of DNA synthesis which was proportional to MICs and MBCs (r > 0.99). Furthermore, 50% inhibition of DNA synthesis and MICs were nearly identical for mutant strains with an altered quinolone target (gyrA) or with decreased [nfxB(ompF)] or increased (acrA) permeability. There were significant differences (P < 0.001) between individual quinolones in the degree of DNA synthesis inhibition in nalidixic acid-resistant gyrA and nfxB(ompF) mutant strains. The comparison of the three mutants with the wild-type strain permitted an in vivo examination of the effects of alterations of the drug target or entry on the activity determined by DNA synthesis inhibition and MICs.

Original languageEnglish (US)
Pages (from-to)1113-1118
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume32
Issue number8
StatePublished - 1988

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Quinolones
Anti-Infective Agents
Escherichia coli
DNA
difloxacin
DNA Gyrase
Norfloxacin
Nalidixic Acid
Ciprofloxacin
Thymidine
Permeability
Cell Death
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

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title = "Association between early inhibiton of DNA synthesis and the MICs and MBCs of carboxyquinolone antimicrobial agents for wild-type and mutant [gyrA nfxB(ompF) acrA] Escherichia coli K-12",
abstract = "Quinolone antimicrobial agents are known to interact with DNA gyrase, but the mechanism by which bacterial cell death occurs is not fully understood. In order to determine whether there is a correlation between quinolone-induced inhibition of early (i.e., 10 to 15 min) DNA synthesis and potency (MICs and MBCs), we measured the rate of DNA synthesis in log-phase Escherichia coli K-12 by using [3H]thymidine incorporation. Three quinolones (ciprofloxacin, norfloxacin, and difloxacin) were selected based on their decreasing activity against reference strain KL16. All three quinolones caused an early 50{\%} inhibition of DNA synthesis which was proportional to MICs and MBCs (r > 0.99). Furthermore, 50{\%} inhibition of DNA synthesis and MICs were nearly identical for mutant strains with an altered quinolone target (gyrA) or with decreased [nfxB(ompF)] or increased (acrA) permeability. There were significant differences (P < 0.001) between individual quinolones in the degree of DNA synthesis inhibition in nalidixic acid-resistant gyrA and nfxB(ompF) mutant strains. The comparison of the three mutants with the wild-type strain permitted an in vivo examination of the effects of alterations of the drug target or entry on the activity determined by DNA synthesis inhibition and MICs.",
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T1 - Association between early inhibiton of DNA synthesis and the MICs and MBCs of carboxyquinolone antimicrobial agents for wild-type and mutant [gyrA nfxB(ompF) acrA] Escherichia coli K-12

AU - Chow, R. T.

AU - Dougherty, T. J.

AU - Fraimow, H. S.

AU - Bellin, Eran Y.

AU - Miller, M. H.

PY - 1988

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AB - Quinolone antimicrobial agents are known to interact with DNA gyrase, but the mechanism by which bacterial cell death occurs is not fully understood. In order to determine whether there is a correlation between quinolone-induced inhibition of early (i.e., 10 to 15 min) DNA synthesis and potency (MICs and MBCs), we measured the rate of DNA synthesis in log-phase Escherichia coli K-12 by using [3H]thymidine incorporation. Three quinolones (ciprofloxacin, norfloxacin, and difloxacin) were selected based on their decreasing activity against reference strain KL16. All three quinolones caused an early 50% inhibition of DNA synthesis which was proportional to MICs and MBCs (r > 0.99). Furthermore, 50% inhibition of DNA synthesis and MICs were nearly identical for mutant strains with an altered quinolone target (gyrA) or with decreased [nfxB(ompF)] or increased (acrA) permeability. There were significant differences (P < 0.001) between individual quinolones in the degree of DNA synthesis inhibition in nalidixic acid-resistant gyrA and nfxB(ompF) mutant strains. The comparison of the three mutants with the wild-type strain permitted an in vivo examination of the effects of alterations of the drug target or entry on the activity determined by DNA synthesis inhibition and MICs.

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