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PubMed1988

In vitro selection of Escherichia coli mutants with decreased susceptibility to norfloxacin.

In 10 clinical isolates of Escherichia coli the frequency of spontaneous mutation to high levels of resistance to nalidixic acid was greater than 300-fold higher than that to norfloxacin. Norfloxacin resistant mutants could not be detected (mutation frequency: less than 10(-12). However, nalidixic acid resistant mutants of E. coli developed decreased susceptibility to norfloxacin at a rate of approximately 10(-9). Mutants with decreased susceptibility to norfloxacin could also be obtained when the same clinical isolates of E. coli were exposed to norfloxacin in 2 steps. However, mutants with MIC values greater than 8 micrograms/ml for norfloxacin were never obtained even after repeated exposure. Widespread use of cinoxacin or nalidixic acid may select resistant strains and reduce the efficacy of norfloxacin and other 4-quinolones.

Drug Resistance, Microbial↗
PubMed1991

Response of V79 cells to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatment: inhibition of poly(ADP-ribose) and topoisomerase activity.

MNNG-induced killing of V79 cells has been found to be enhanced on inhibition of topoisomerase II activity by nalidixic acid and poly(ADP-ribose) polymerase synthesis by benzamide. Using these 2 inhibitors in conjunction after MNNG treatment, some overlap in the functions of these 2 enzymes was observed. Nalidixic acid and benzamide were found to suppress the yields of mutations and SCEs induced by MNNG. Benzamide was more effective in suppressing the mutation yield whereas nalidixic acid was more effective in suppressing SCEs. A model based on the relative requirement of topoisomerase and poly(ADP-ribose) for the repair of different types of damage has been proposed to explain the results.

Adenosine Diphosphate Ribose↗
PubMedDate not supplied

Antimutagenesis of beta-carotene to mutations induced by quinolone on Salmonella typhimurium.

BACKGROUND: Quinolone-induced mutagenesis in the Salmonella typhimurium hisG48 strains suggests that these antibiotics are oxygen free radical generators. The use of beta-carotene as antioxidant was evaluated as an alternative to reduce oxidative cell damage in patients who need therapy with nalidixic acid, norfloxacin, or pipemidic acid. The studied beta-carotene (30%), used by pharmaceutical laboratories as dietary complements, was not toxic or mutagenic for the S. typhimurium TA102 strain at a dose equivalent to 1,500 I.U. At the studied concentrations, the evaluated antimutagen did not modify the minimum inhibitory concentration of nalidixic acid, norfloxacin, or pipemidic acid against uropathogenic Escherichia coli strains. METHODS: The mutagenic effect of nalidixic acid and norfloxacin against hisG48 strains was inhibited with 1500 I.U. of beta-carotene. The antimutagenic effect of beta-carotene against mutations induced by pipemidic acid was observed even with 150 I.U. of beta-carotene. The antimutagenic effect against mutations induced on S. typhimurium TA102 or TA104 strains was observed only when the aroclor 1254 rat-induced liver S9 mixture was used. RESULTS: This mutagenic effect was detected only when the strains were exposed to quinolones and the beta-carotene simultaneously with the S9 mixture, suggesting that quinolones induce oxygen free radicals that may be scavenged by beta-carotene. CONCLUSIONS: The antimutagenic effect of this vitamin A precursor is probably due to the active molecule of vitamin A, a desmutagen with the ability of radical capture. A diet rich in beta-carotene or vitamin A could be a good alternative to reduce genotoxic risk to patients being treated with quinolone.

Animals↗
PubMed1984

Campylobacter laridis causing bacteremia in an immunosuppressed patient.

An unusual species, Campylobacter laridis , belonging to the group of nalidixic acid resistant thermophilic Campylobacter species, was isolated from the blood of a 71-year-old man with multiple myeloma, hyperviscosity syndrome, and renal failure. The organism was first recognized in the laboratory by gram-stain reaction and resistance to nalidixic acid. The organism differs from C. jejuni and C. coli by its resistance to nalidixic acid, whereas anaerobic growth in the presence of trimethylamine N-oxide hydrochloride differentiates this organism from other Campylobacter species. Biochemical characterization and DNA homology studies confirmed the identity of this species as being C. laridis . To our knowledge, this is the first recorded case of bacteremia due to C. laridis in humans.

Aged↗
PubMed1968

Regulation of deoxyribonucleic acid replication and cell division in Escherichia coli B-r.

Synchronous cultures of Escherichia coli strain B/r were used to investigate the relationship between deoxyribonucleic acid (DNA) replication and cell division. We have determined that terminal steps in division can proceed in the absence of DNA synthesis. Inhibition of DNA replication with nalidixic acid prior to the start of a new round of replication does not stop cell division, which indicates that the start of the round is not essential in triggering cell division. Inhibition of DNA replication at any time prior to the termination of a round of replication completely blocks cell division, which suggests that there may be a link between the end of the replication cycle and the commitment of the cell to divide. Studies that use a temperature-sensitive mutant which is unable to synthesize DNA at the nonpermissive temperature are in complete agreement with those that use nalidixic acid to inhibit DNA synthesis. This adds support to the idea that the treatments employed limit their action to DNA synthesis. Investigation of minicell production indicates that the production of minicells is blocked when DNA synthesis is inhibited with nalidixic acid. Although nuclear segregation is not required for cell division, DNA synthesis is still required to trigger division. The evidence presented suggests strongly that (i) DNA synthesis is essential for cell division, (ii) the end of a round of replication triggers cell division, and (iii) there is considerable time lapse (one-half generation) between the completion of a round of DNA replication and physical separation of the cells.

Carbon Isotopes↗
PubMed2004

Increasing prevalence of quinolone resistance in human nontyphoid Salmonella enterica isolates obtained in Spain from 1981 to 2003.

From January 1981 to December 2003, susceptibility to nalidixic acid was tested in 10,504 nontyphoid Salmonella enterica isolates from patients with acute enteric disease in Gipuzkoa, Spain. The prevalence of nalidixic acid resistance steadily increased from less than 0.5% before 1991 to 38.5% in 2003, mainly due to the increase in resistance among isolates of the most prevalent serovar, S. enterica serovar Enteritidis. For nalidixic acid-resistant isolates, the ciprofloxacin MIC was eightfold higher than that for susceptible isolates, and the nalidixic acid-resistant isolates contained a single point mutation in the gyrA gene (at codons for Ser83 or Asp87). The same mutations were found in a sample of nalidixic acid-resistant nontyphoid Salmonella strains isolated between 1999 and 2003 from retail food for human consumption. In 2003, we identified five S. enterica serovar Typhimurium clinical isolates with high-level fluoroquinolone resistance (ciprofloxacin MIC, 16 microg/ml) with two point mutations in the gyrA gene (coding for Ser83-->Phe and Asp87-->Asn) and one point mutation in the parC gene (coding for Ser80-->Arg). Strict sanitary controls are needed to avoid the spread of ciprofloxacin-resistant serovar Typhimurium isolates, and a more efficient veterinary policy must be adopted to decrease the large burden of Salmonella serovar Enteritidis infections in humans in our region.

Anti-Infective Agents↗
PubMed1996

Increase in synthesis and stability of sigma 32 on treatment with inhibitors of DNA gyrase in Escherichia coli.

We report here that in Escherichia coli, the anti-bacterial agent nalidixic acid induces transient stabilization and increased synthesis of sigma 32, accompanied by the induction of heat shock proteins (Dnak and GroEL proteins). The induction of heat shock proteins, increased synthesis of sigma 32, and stabilization of sigma 32 observed on treatment of wild-type cells with nalidixic acid were not observed in a nalA26 mutant, a strain that is resistant to nalidixic acid as the result of a mutation in the gyrA gene. Not only oxolinic acid, but also novobiocin, whose targets are the A and B subunits of DNA gyrase, respectively, also induced stabilization and increased synthesis of sigma 32. Thus, inhibition of the activity of DNA gyrase may cause stabilization and increased synthesis of sigma 32, resulting in turn in induction of heat shock proteins.

Anti-Infective Agents↗
PubMed1978

Purification of subunits of Escherichia coli DNA gyrase and reconstitution of enzymatic activity.

Extensively purified DNA gyrase from Escherichia coli is inhibited by nalidixic acid and by novobiocin. The enzyme is composed of two subunits, A and B, which were purified as separate components. Subunit A is the product of the gene controlling sensitivity to nalidixic acid (nalA) because: (i) the electrophoretic mobility of subunit A in the presence of sodium dodecyl sulfate is identical to that of the 105,000-dalton nalA gene product; (ii) mutants that are resistant to nalidixic acid (nalA(r)) produce a drug-resistant subunit A; and (iii) wild-type subunit A confers drug sensitivity to in vitro synthesis of varphiX174 DNA directed by nalA(r) mutants. Subunit B contains a 95,000-dalton polypeptide and is controlled by the gene specifying sensitivity to novobiocin (cou) because cou(r) mutants produce a novobiocin-resistant subunit B and novobiocin-resitant gyrase is made drug sensitive by wild-type subunit B. Subunits A and B associate, so that gyrase was also purified as a complex containing 105,000- and 95,000-dalton polypeptides. This enzyme and gyrase reconstructed from subunits have the same drug sensitivity, K(m) for ATP, and catalytic properties. The same ratio of subunits gives efficient reconstitution of the reactions intrinsic to DNA gyrase, including catalysis of supercoiling of closed duplex DNA, relaxation of supercoiled DNA in the absence of ATP, and site-specific cleavage of DNA induced by sodium dodecyl sulfate.

DNA, Bacterial↗
PubMed2006

Resistance to three antimicrobial agents of Campylobacter isolated from organically- and intensively-reared chickens purchased from retail outlets.

Resistance rates to three antimicrobials (ciprofloxacin, erythromycin and nalidixic acid) in Campylobacter isolated from organically- and intensively-reared chickens purchased from supermarkets and butcher's shops in London were determined. Significant differences in the minimum inhibitory concentrations (MICs) of nalidixic acid were found, with the highest values in unpackaged intensively-reared chickens and the lowest values in organically-reared chickens. Using pre-set breakpoints, all isolates from all groups of chickens were identified as resistant to erythromycin and nalidixic acid. All isolates from the organically-reared group were susceptible to ciprofloxacin. Of the supermarket intensively-reared chickens, 8.7% harboured resistant isolates, all on the external parts, indicating post-slaughtering contamination. The highest percentage (26.7%) was in chickens from butcher shops, mostly in the chicken cavities, suggesting a link to treatment on the farm.

Animal Husbandry↗
PubMed1990

DNA breakdown by the 4-quinolones and its significance.

DNA breakdown occurred in Escherichia coli KL16 exposed to nalidixic acid, ciprofloxacin or norfloxacin. However DNA breakdown does not seem to be the cause of the lethality of the 4-quinolones because it still occurred under conditions which abolished the lethality of nalidixic acid. Furthermore, no correlation was found between the amount of DNA breakdown and the rate of death of bacteria caused by the three 4-quinolones. Similarly, DNA breakdown did not occur when recB or recC mutants were treated with nalidixic acid despite both mutants being killed by the drug, again suggesting that DNA breakdown is not the cause of bacterial death. Since recB and recC mutants lack exonuclease V, this enzyme may be responsible for the DNA breakdown observed in bacteria treated with 4-quinolones.

Ciprofloxacin↗
PubMed1999

Analysis of the mechanisms of quinolone resistance in clinical isolates of Citrobacter freundii.

The presence of gyrA, gyrB and/or parC mutations, quinolone uptake, outer membrane protein profiles and epidemiological relationship were studied in 12 clinical isolates of Citrobacter freundii. No alterations were observed in the gyrB gene of any of the strains, or gyrA or parC of the four quinolone-susceptible strains (nalidixic acid MIC of 2-4 mg/L, and a ciprofloxacin MIC of 0.006-0.06 mg/L). The quinolone-resistant strains were classified into two groups: one group (group A) composed of strains resistant to nalidixic acid but not to ciprofloxacin and another (group B) including those resistant to both antibiotics with a mutation at codon 83 of the gyrA gene (Thr-->Ile), but no alteration in either parC or gyrB genes. In group B, three of the four resistant isolates, with a nalidixic acid MIC > 1024 mg/L and ciprofloxacin MIC of 8-32 mg/L, showed concomitant mutations at codons 83 and 87 of the gyrA gene (Thr-->Ile and Asp-->Tyr, respectively) as well as a single mutation in codon 80 of the parC gene (Ser-->Ile). The fourth isolate did not possess the mutation at codon 87 of gyrA. Two strains belong to the same clone and, although they had the same type of mutations in the gyrA and parC genes, showed different MICs of ciprofloxacin. This difference was related to an efflux pump mechanism. Mutations in the gyrA and parC genes play the main role in quinolone resistance development in Citrobacter freundii, although other factors such as overexpression of efflux pumps can play a complementary role and thus modulate the final quinolone MIC.

Amino Acid Sequence↗
PubMed1979

Escherichia coli mutants thermosensitive for deoxyribonucleic acid gyrase subunit A: effects on deoxyribonucleic acid replication, transcription, and bacteriophage growth.

Temperature-sensitive nalA mutants of Escherichia coli have been used to investigate the structure and functions of deoxyribonucleic acid (DNA) gyrase. Extracts of one such mutant (nalA43) had thermosensitive DNA gyrase subunit A activity but normal gyrase subunit B activity, proving definitively that nalA is the structural gene for subunit A. Extracts of a second nalA (Ts) mutant (nalA45) had a 50-fold deficiency of gyrase subunit A activity. The residual DNA supertwisting was catalyzed by the mutant DNA gyrase rather than by a novel supertwisting enzyme. The nalA45(Ts) extract was also deficient in the nalidixic acid target, which is defined as the protein necessary to confer drug sensitivity to in vitro DNA replication directed by a nalidixic acid-resistant mutant extract. Thus, gyrase subunit A and the nalidixic acid target are one and the same protein, the nalA gene product. Shift of the nalA43(Ts) mutant to a nonpermissive temperature resulted in a precipitous decline in the rate of [(3)H]thymidine incorporation, demonstrating an obligatory role of the nalA gene product in DNA replication. The rates of incorporation of [(3)H]uridine pulses and continuously administered [(3)H]uracil were quickly reduced approximately twofold upon temperature shift of the nalA43(Ts) mutant, and therefore some but not all transcription requires the nalA gene product. The thermosensitive growth of bacteriophages phiX174 and T4 in the nalA43(Ts) host shows that these phages depend on the host nalA gene product. In contrast, the growth of phage T7 was strongly inhibited by nalidixic acid but essentially unaffected by the nalA43(Ts) mutation. The inhibition of T7 growth by nalidixic acid was, however, eliminated by temperature inactivation of the nal43 gene product. Therefore, nalidixic acid may block T7 growth by a corruption rather than a simple elimination of the nalidixic acid target. Possible mechanisms for such a corruption are considered, and their relevance to the puzzling dominance of drug sensitivity is discussed.

Coliphages↗
PubMed1989

Serum protein binding of lomefloxacin, a new antimicrobial agent, and its related quinolones.

The serum protein binding of lomefloxacin (LFLX), a new quinolone (pyridonecarboxylic acid), and its related analogues was studied by an ultrafiltration technique. The extent of binding of quinolones was independent of the concentration of quinolones below 100 micrograms/mL in rat serum; but, above this concentration, the binding decreased with increased drug concentration in the case of nalidixic acid and analogue 3. The extent of binding in rat serum differed widely among the quinolones examined [i.e., from 15% (norfloxacin) to 84% (nalidixic acid) at concentrations of 0.4-10.0 micrograms/mL]. Lomefloxacin was bound to serum proteins to the extent of 28.1, 20.1, and 20.6% in the sera of rats, dogs, and humans, respectively. The binding of nalidixic acid with rat serum albumin, which was very similar to that in rat serum, was concentration dependent. Some quinolone derivatives with a piperazinyl group or a relatively large-sized substituent at the 7-position exhibited a percentage unbound of approximately 70-80%, while some derivatives with small-sized substituents gave a low percentage unbound of 20-30%. This suggests that there is a steric effect of the substituents at the 7-position of quinolones on their binding characteristics with serum proteins. The results of the present study indicate that quinolones bind mainly with albumin among serum proteins and that the remarkable difference of the extent of binding of quinolone analogues is related to the size of the substituent at the 7-position of the molecule, possibly due to its steric effect.

Animals↗
PubMed1997

Comparison of disc diffusion and agar dilution methods for antibiotic susceptibility testing of Campylobacter jejuni subsp. jejuni and Campylobacter coli.

The correlation between disc diffusion and agar dilution susceptibility testing of five antibiotics was studied against 145 Campylobacter strains: 99 Campylobacter jejuni subsp. jejuni and 46 Campylobacter coli. The percentages of true results and 95% CI for disc diffusion for resistant strains were 100% (93.2-100%) for tetracycline (53 strains tested), 100% (77.2-100%) for ciprofloxacin (13 strains tested), 86.7% (62.1-96.3%) for nalidixic acid (15 strains tested), 100% (56.6-100%) for erythromycin (five strains tested) and 68.8% (44.4-85.8%) for ampicillin (16 strains tested). The percentages of true results and 95% CI were 97.6-100% and 93.2-100% respectively for 89-140 susceptible strains to the five antibiotics tested. There was a 1.4% major error for nalidixic acid, 0.7% very major error for erythromycin, 5.5% and 1.4% minor and major errors respectively for ampicillin. There was complete agreement for ciprofloxacin and tetracycline. Results of ampicillin susceptibility are not expected to be useful in a clinical setting. The nalidixic acid disc is a marker of ciprofloxacin susceptibility as the nalidixic acid-susceptible strains were susceptible to ciprofloxacin while most of the resistant ones were resistant to ciprofloxacin. Overall, our results suggest that disc diffusion is a reliable, easy and inexpensive susceptibility testing method for C. jejuni and C. coli for erythromycin, ciprofloxacin and tetracycline. Until more erythromycin- and ciprofloxacin-resistant strains are tested to confirm the reliability of this test, the resistance to these drugs needs to be confirmed using the Etest or the agar dilution method.

Ampicillin↗
PubMed1997

DNA gyrase involvement in chloroplast-nucleoid division in Cyanidioschyzon merolae.

Cyanidioschyzon merolae is a unicellular alga with one chloroplast and one mitochondrion per cell. Each of these organelles has a simple nucleoid located in the central area. Prior to mitosis and cytokinesis, both the division of organelle nucleoids and organellokinesis occur simultaneously. We investigated the effects of nalidixic acid, an inhibitor of DNA gyrase, on the replication and division of organelle nucleoids. Using microfluorometry, we monitored the synthesis of organelle DNA (organelle S phase) in synchronous cultures. In both the chloroplast and the mitochondrion, DNA synthesis occurred from the start of the light period and ceased within 3 h. The addition of nalidixic acid at the start of the light period inhibited DNA synthesis in both organelles. Next, we added nalidixic acid to the synchronous culture at the beginning (just before the organelle S phase) or at the end (organelle G2 phase) of the light period and monitored the division of organelle nucleoids in the dark period. Approximately 50 to 70% of chloroplast nucleoids divided unequally in both experiments. Despite the unequal division of the chloroplast nucleoids, electron microscopy revealed that the chloroplasts were divided into equal daughter chloroplasts by the chloroplast-divided ring. During the same treatments, all of the mitochondrial nucleoids underwent normal and equal division. Our results suggest the involvement of DNA gyrase in the replication of chloroplast and mitochondrial DNA and in the division of the chloroplast nucleoid, as well as a difference in mechanism between the division of chloroplast and mitochondrial nucleoids.

Anti-Infective Agents↗
PubMed2001

Evaluation of a selective broth for detection of Staphylococcus aureus using impedance microbiology.

Experiments were conducted to evaluate a selective nutrient broth containing acriflavine and nalidixic acid for detection of Staphylococcus aureus using an impedance microbiological method. Nine species of bacteria, other than S. aureus, were evaluated using the selective broth to determine if these species could be inhibited. A total of 10 ppm of nalidixic acid inhibited the gram-negative species tested, with the exception of Pseudomonas aeruginosa. Similarly, 10 ppm of acriflavine suppressed the Staphylococcus spp. examined; however, S. aureus retained the ability to proliferate. Nutrient broth solution containing 10 ppm of nalidixic acid and 10 ppm of acriflavine (S. aureus impedance broth [SIB]) inhibited multiplication of most of the bacterial species tested and allowed S. aureus to be detected in an average of 16.4 h. Fresh chicken carcass rinses and cooked chicken rinses were inoculated with Escherichia coli and S. aureus and assayed using SIB in conjunction with impedance. Results demonstrated that S. aureus could be detected in less than 11.5 h, although the presence of E. coli decreased detection times. Additionally, impedance assays were conducted using five different poultry products to evaluate the sensitivity of the broth for detecting S. aureus. S. aureus could be detected on poultry products when present at low levels (10(1) CFU/ml) in less than 24 h. These studies demonstrated that SIB may be used in conjunction with impedance for rapid detection of S. aureus. However, without further modification, this method should not be used for enumeration of S. aureus from samples containing mixed microflora.

Acriflavine↗
PubMed1999

Quinolone accumulation by Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli.

The accumulation of nalidixic acid and 14 fluoroquinolones over a range of external drug concentrations (10-100 mg/L; c. 25-231 microM) into intact cells of Escherichia coli KL-16, Staphylococcus aureus NCTC 8532, Pseudomonas aeruginosa NCTC 10662 and spheroplasts of E. coli was investigated. The effect of 100 microM carbonyl cyanide m-chlorophenyl hydrazone (CCCP) upon the concentration of quinolone accumulated by intact cells and spheroplasts of E. coli was also determined. Except for pefloxacin, there was an increase in the concentration of the six quinolones examined accumulated by E. coli, despite a reduction in fluorescence at alkaline pH. For ciprofloxacin the partition coefficient (P(app)) was constant despite an increase in the pH; however, the P(app) for nalidixic acid decreased significantly with an increase in pH. The concentration of nalidixic acid, ciprofloxacin and enrofloxacin accumulated by E. coli and S. aureus increased with an increase in temperature up to 40 degrees C and 50 degrees C, respectively. Above these temperatures the cell viability decreased. With an increase in drug concentration there was, for intact E. coli and 12/15 agents, and for S. aureus and 10/15 agents, a linear increase in the concentration of drug accumulated. However, for P. aeruginosa and 13/15 agents there was apparent saturation of an accumulation pathway. Assuming 100% accumulation into intact cells of E. coli, for 10/14 fluoroquinolones < or = 40% was accumulated by spheroplasts. CCCP increased the concentration of quinolone accumulated but the increase varied with the agent and the bacterial species. The variation in the effect of CCCP upon accumulation of the different quinolones into E. coli could result from chemical interactions or from different affinities of the proposed efflux transporter for each quinolone. Overall, these data suggest that accumulation of most quinolones into E. coli and S. aureus proceeds by simple diffusion, but that P. aeruginosa behaves differently.

Anti-Infective Agents↗