Studies on the Mechanism of Action of Nalidixic Acid

Bourguignon, Gerard J.; Levitt, Martin; Sternglanz, Rolf

doi:10.1128/aac.4.4.479

Cited by 95 publications

(38 citation statements)

References 23 publications

(19 reference statements)

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“…The purpose of this investigation was to establish whether the developmental cycle of R. palustris was arrested or modified after inhibition of DNA synthesis, and hence what morphological stages might depend on chromosome replication. Although there has been little success in elucidating the mode of action of NAL (Boyle, Cook & GOSS, 1969;Bourguignon, Levitt & Sternglanz, 1973) it does have the advantage over other inhibitors of DNA synthesis that its action is rapidly reversible (Ward, Hane & Glaser, 1970). Thymine starvation could not be used as a means of inhibiting DNA synthesis as we have not been able to obtain any thymine-requiring mutants of R. palustris.…”

Section: Westmacott and S B Primrosementioning

confidence: 94%

The Effect of Nalidixic Acid on the Cell Cycle of Synchronous Rhodopseudomonas palustris Cultures

Westmacott¹,

Primrose²

1977

Journal of General Microbiology

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The influence of the DNA synthesis inhibitor, nalidixic acid, on the properties of synchronous cultures of selected Rhodopseudomonas palustris swarmer cells was examined. There was little alteration in the changes in morphology, extinction, volume distribution and leucine incorporation up to bud development, and photosynthetic membrane lamellae were still synthesized de novo in the bud. However, there was no subsequent division, or flagellum or holdfast synthesis. Instead cells elongated by continued outgrowth of the abortive bud. Since DNA synthesis was also inhibited, this suggested a dependence of cell division, and flagellum and holdfast synthesis, on the completion of chromosome replication. By addition or removal of nalidixic acid at various times in the cell cycle, periods were demonstrated when the organism was insensitive to the antibiotic indicating that there was a pre-synthetic and post-synthetic gap in the pattern of DNA synthesis in R. palustris swarmers.

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Section: Westmacott and S B Primrosementioning

confidence: 94%

The Effect of Nalidixic Acid on the Cell Cycle of Synchronous Rhodopseudomonas palustris Cultures

Westmacott¹,

Primrose²

1977

Journal of General Microbiology

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“…Benbrook and Miller (3). Some experiments were carried with EDTA-permeabilized cells (6), except that incubation in the presence of 0.2 mM EDTA was limited to 1 min (instead of 2 min in the original method used for Escherichia coli).…”

Section: Methodsmentioning

confidence: 99%

Resistance to pefloxacin in Pseudomonas aeruginosa

Michéa-Hamzehpour

Lucain

Péchère

1991

Antimicrob Agents Chemother

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Mechanisms of resistance to pefloxacin were investigated in four isogenic Pseudomonas aeruginosa strains: S (parent isolate; MIC, 2 ,ug/ml), PT1 and PT2 (posttherapy isolates obtained in animals; MICs, 32 and 128 ,ug/ml, respectively), and PT2-r (posttherapy isolate obtained after six in vitro subpassages of PT2; MIC, 32 ,ug/ml). [2-3H]adenine incorporation (indirect evidence of DNA gyrase activity) in EDTA-permeabilized cells was less affected by pefloxacin in PT2 and PT2-r (50% inhibitory concentration, 0.27 and 0.26 ,ug/ml, respectively) than it was in S and PT1 (50% inhibitory concentration, 0.04 and 0.05 ,ug/ml, respectively). Reduced [14C]pefloxacin labeling of intact cells in strains PT1 and PT2 correlated with more susceptibility to EDTA and the presence of more calcium (P < 0.05) and phosphorus in the outer membrane fractions. Outer membrane protein analysis showed reduced expression of protein D2 (47 kDa) in strains PT1 and PT2. Other proteins were apparently similar in all strains. The addition of calcium chloride (2 mM) to the sodium dodecyl sulfate-solubilized samples of outer membrane proteins, before heating and Western blotting, probed with monoclonal antibody anti-OmpF showed electrophoretic mobility changes of OmpF in strains PT1 and PT2 which were not seen in strain S. Calcium-induced changes were reversed with ethyleneglycoltetraacetate.Decreased [14C]pefloxacin labeling was further correlated with an altered lipopolysaccharide pattern and increased 3-deoxy-D-mannooctulosonic acid concentration (P < 0.01). These findings suggested that resistance to pefloxacin is associated with altered DNA gyrase in strain PT2-r, with altered permeability in PT1, and with both mechanisms in PT2. The decreased expression of protein D2 and the higher calcium and lipopolysaccharide contents of the outer membrane could be responsible for the permeability deficiency in P. aeruginosa.The activities of fluoroquinolones against Pseudomonas aeruginosa have been fully documented (45), but bacteria can develop resistance to these agents (12,18,19,36,38). This resistance results from reduced permeability of the outer membrane (OM), altered DNA gyrase, or a combination of the two processes (7,8,18,36,38). However, mechanisms of resistance at the molecular level are not yet entirely elucidated (45).In a pseudomonal peritonitis model, we showed previously that resistance emerges rapidly when mice are treated with pefloxacin or ciprofloxacin (26). In mice infected with a quinolone-susceptible P. aeruginosa isolate, posttherapy variants (strain PT1) emerged after a single dose of pefloxacin, showing an 8-to 16-fold decrease in susceptibility to quinolones. Subinoculation of a PT1 strain, followed by therapeutic exposure to ciprofloxacin, produced a highly resistant posttherapy variant (strain PT2) for which the MIC was increased 64-fold (26).We report here results of further studies on the mechanism of resistance of these strains. As expected, we observed involvements of DNA gyrase and permeability, but we were surprised by ...

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“…These results suggest that other factors contribute to resistance in GN16598. Alteration in outer membrane permeability is another potential mechanism of resistance to quinolones (2,6,19). Resistance to quinolones is associated with pleiotrophic resistance to nonquinolone agents and with changes in outer membrane proteins in Klebsiella pneumoniae.…”

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confidence: 99%