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PubMed1989

4-quinolones and the SOS response.

The SOS DNA repair system is induced in bacteria treated with 4-quinolones. However, whether the response exacerbates or repairs the damage caused by these drugs is still unclear. The recA13 and the recB21 mutations impair recombination repair and render bacteria unable to induce the SOS response when treated with nalidixic acid or other agents that affect DNA synthesis. However, UV treatment induces the SOS response in recB21 mutants but not in recA13 mutants. Both these mutants are hypersensitive to nalidixic acid and, therefore, either recombination repair or SOS repair would appear to repair DNA damage caused by the drug. However, since the lexA3 mutation (which also renders bacteria incapable of inducing the SOS response without affecting recombination repair) had no effect on the susceptibility of bacteria to nalidixic acid, the SOS response neither contributes to nor repairs DNA damage caused by the drug. Consequently, it would seem that the hypersensitivity of the recA13 and recB21 mutants to nalidixic acid is due to their deficiency in recombination repair. This view was confirmed by testing a recA430 mutant that is recombination-repair proficient but SOS repair-deficient and finding it to be no more sensitive to nalidixic acid than its parent. Thus it would appear that, although induced by nalidixic acid treatment, the SOS DNA repair system does not play any role in bacterial responses to the damage caused by the drug. In contrast, the recombination repair system does repair damage caused by nalidixic acid.

Anti-Infective Agents↗

PubMed1987

Isolation and characterization of novobiocin-resistant BHK cells.

We isolated two novobiocin-resistant mutants which were stable and approximately three and four times more resistant than the parent cells to novobiocin. Both mutants (Novr A2, Novr A41) were more sensitive than the wild-type cells to nalidixic acid, and cold sensitive for cell growth. When we isolated derivatives of Novr A2 and Novr A41 cells which are resistant to nalidixic acid, those are found to be phenotypically reverted to novobiocin sensitivity like wild-type cells, thereby suggesting the relationship between the targets for novobiocin and for nalidixic acid. But the cold sensitivity did not always revert to wild type, with accompanying resistance to nalidixic acid. The DNA and RNA syntheses of Novr mutants were more resistant to novobiocin but more sensitive to nalidixic acid, than those of wild-type cells. However, in vitro assays of wild-type and Novr cell extracts were unable to demonstrate any differences in the sensitivity of topoisomerase II activity to inhibition by novobiocin. While the targets of novobiocin and nalidixic acid show a mutual interaction in vivo and play a role in DNA replication and transcription, our results suggest that these targets are probably not topoisomerase II.

Animals↗

PubMed1990

Rapid detection of chlorine-induced bacterial injury by the direct viable count method using image analysis.

A modified direct viable count method to detect living bacteria was used with image analysis for the rapid enumeration of chlorine-injured cells in an Escherichia coli culture. The method was also used for determining chlorine-induced injury in coliform isolates and enteric pathogenic bacteria. Cultures were incubated in phosphate-buffered saline, containing 0.3% Casamino Acids (Difco Laboratories, Detroit, Mich.), 0.03% yeast extract, and optimal concentrations of nalidixic acid. Samples were withdrawn before and after incubation and stained with acridine orange, and cell lengths and breadths were measured by computerized image analysis. After incubation, cells which exceeded the mean preincubation length (viable cells) were enumerated and the results were compared with those obtained by the plate count method. Injury in the chlorine-exposed cell population was determined from the difference in viable count obtained with a nonselective Casamino Acids-yeast extract-nalidixic acid medium and a selective Casamino Acids-yeast extract-nalidixic acid medium containing sodium deoxycholate or sodium lauryl sulfate. The levels of injury determined by the direct viable count technique by using image analysis were comparable to those determined by the plate count method. The results showed that image analysis, under optimal conditions, enumerated significantly higher numbers of stressed E. coli than the plate count method did and detected injury in various cultures in 4 to 6 h.

Chlorine↗

PubMed2005

Clinical outcomes in typhoid fever: adverse impact of infection with nalidixic acid-resistant Salmonella typhi.

BACKGROUND: Widespread use of fluoroquinolones has resulted in emergence of Salmonella typhi strains with decreased susceptibility to fluoroquinolones. These strains are identifiable by their nalidixic acid-resistance. We studied the impact of infection with nalidixic acid-resistant S. typhi (NARST) on clinical outcomes in patients with bacteriologically-confirmed typhoid fever. METHODS: Clinical and laboratory features, fever clearance time and complications were prospectively studied in patients with blood culture-proven typhoid fever, treated at a tertiary care hospital in north India, during the period from November 2001 to October 2003. Susceptibility to amoxycillin, co-trimoxazole, chloramphenicol, ciprofloxacin and ceftriaxone were tested by disc diffusion method. Minimum inhibitory concentrations (MIC) of ciprofloxacin and ceftriaxone were determined by E-test method. RESULTS: During a two-year period, 60 patients (age [mean +/- SD]: 15 +/- 9 years; males: 40 [67%]) were studied. All isolates were sensitive to ciprofloxacin and ceftriaxone by disc diffusion and MIC breakpoints. However, 11 patients had clinical failure of fluoroquinolone therapy. Infections with NARST isolates (47 [78%]) were significantly associated with longer duration of fever at presentation (median [IQR] 10 [7-15] vs. 4 [3-6] days; P = 0.000), higher frequency of hepatomegaly (57% vs. 15%; P = 0.021), higher levels of aspartate aminotransferase (121 [66-235] vs. 73 [44-119] IU/L; P = 0.033), and increased MIC of ciprofloxacin (0.37 +/- 0.21 vs. 0.17 +/- 0.14 microg/mL; P = 0.005), as compared to infections with nalidixic acid-susceptible isolates. All 11 patients with complications were infected with NARST isolates. Total duration of illness was significantly longer in patients who developed complications than in patients who did not (22 [14.8-32] vs. 12 [9.3-20.3] days; P = 0.011). Duration of prior antibiotic intake had a strong positive correlation with the duration of fever at presentation (r = 0.61; P = 0.000) as well as the total duration of illness (r = 0.53; P = 0.000). CONCLUSION: Typhoid fever caused by NARST infection is associated with poor clinical outcomes, probably due to delay in initiating appropriate antibiotic therapy. Fluoroquinolone breakpoints for S. typhi need to be redefined and fluoroquinolones should no longer be used as first-line therapy, if the prevalence of NARST is high.

Adolescent↗

PubMed2003

Antimicrobial resistance in clinical isolates of Salmonella enterica serotype Enteritidis: relationships between mutations conferring quinolone resistance, integrons, plasmids and genetic types.

In 481 clinical isolates of Salmonella enterica serotype Enteritidis collected from a Spanish region in 2000, 108, 83 and four isolates were resistant, respectively, to nalidixic acid, ampicillin or both. Nalidixic acid resistance was the result of DNA gyrase mutations involving the codons Asp-87 (97 isolates) and Ser-83 (15 isolates) of the gyrA gene; no mutations in parC were detected. In ampicillin-resistant strains, blaTEM genes located on plasmids and/or the chromosome were implicated. Five plasmids containing blaTEM1-like genes were identified, ranging from 7 to 100 kb, four of which were self-transferable; one of these contained a class 1 sul1 integron with an aadA1a gene cassette. This integron was also found on the chromosome of an isolate resistant to ampicillin, streptomycin and sulfadiazine. A relationship between a 40 kb self-transferable plasmid and strains of Salmonella Enteritidis phage type 6a with a distinctive RAPD profile was established.

Ampicillin↗

PubMed1987

[Research on antibacterial and antifungal agents. VII. Synthesis of (1-pyrryl)methylquinolines acids].

Some (1-pyrryl)methyl derivatives of 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were synthetized by the standard procedure involving Gould-Jacobs and Lappin reactions. The above derivatives were tested microbiologically as nalidixic acid analogs and compared with some clinically useful 4-oxopyridine-3-carboxylic acids (nalidixic acid, pipemidic acid, norfloxacin, enoxacin and ciprofloxacin). Their antibacterial activities were very weak.

Anti-Bacterial Agents↗

PubMed1997

A novel, double mutation in DNA gyrase A of Escherichia coli conferring resistance to quinolone antibiotics.

A spontaneous Escherichia coli mutant, named Q3, resistant to nalidixic acid was obtained from a previously described clinical isolate of E. coli, Q2, resistant to fluoroquinolones but susceptible to nalidixic acid (E. Cambau, F. Bordon, E. Collatz, and L. Gutmann, Antimicrob. Agents Chemother. 37:1247-1252, 1993). Q3 harbored the mutation Asp82Gly in addition to the Gly81Asp mutation of Q2. The different mutations leading to Gly81Asp, Asp82Gly, and Gly81AspAsp82Gly were introduced into the gyrA gene harbored on plasmid pJSW102, and the resulting plasmids were introduced into E. coli KNK453 (gyrAts) by transformation. The presence of Asp82Gly or Gly81Asp alone led to a low-level resistance to fluoroquinolones but not to nalidixic acid resistance. When both mutations were present, resistance to both nalidixic acid and fluoroquinolones was expressed. Purified gyrases of the different mutants showed similar rates of supercoiling. Dominance of the various gyrA mutant alleles harbored on plasmids was examined. The susceptibility to quinolones associated with wild-type gyrA was always dominant. The susceptibility to nalidixic acid expressed by the Gly81Asp mutant was dominant, while that expressed by the Asp82Gly mutant was recessive. From these results, we hypothesize that some amino acids within the quinolone resistance-determining region of gyrase A are more important for the association of subunits rather than for the activity of the holoenzyme.

Anti-Infective Agents↗

PubMed1985

Plasmid characterization of drug-resistant Shigella dysenteriae 1 from an epidemic in Central Africa.

A widespread epidemic of severe dysentery in Zaire and neighbouring Central African countries was caused by a multiply drug-resistant strain of Shigella dysenteriae 1. Early isolations were resistant to ampicillin, chloramphenicol, streptomycin, sulphonamides and tetracyclines (R-type = ACSSuT). Later in the epidemic strains resistant to trimethoprim (Tm) became prevalent and a few strains resistant to kanamycin (K) or nalidixic acid were also isolated. All resistances except nalidixic acid were encoded by plasmids of incompatibility groups X (ACT) or I1 (ACSSuTTm) and the epidemic strain also carried an SSu plasmid and a number of cryptic plasmids. The Inc X plasmid from this epidemic is the same as that in Sh. dysenteriae 1 strains isolated in Somalia in 1976 whereas the epidemic strains from the Shiga outbreaks in Central America, 1969 to 1971, and Sri Lanka, 1979, carried plasmids of group B. This epidemic demonstrates that when a multiresistant strain includes resistance to trimethoprim, nalidixic acid is a suitable alternative therapeutic agent.

Africa, Central↗

PubMed2006

Lethal fragmentation of bacterial chromosomes mediated by DNA gyrase and quinolones.

When DNA gyrase is trapped on bacterial chromosomes by quinolone antibacterials, reversible complexes form that contain DNA ends constrained by protein. Two subsequent processes lead to rapid cell death. One requires ongoing protein synthesis; the other does not. The prototype quinolone, nalidixic acid, kills wild-type Escherichia coli only by the first pathway; fluoroquinolones kill by both. Both lethal processes correlated with irreversible chromosome fragmentation, detected by sedimentation and viscosity of DNA from quinolone-treated cells. However, only fluoroquinolones fragmented purified nucleoids when incubated with gyrase purified from wild-type cells. A GyrA amino acid substitution (A67S) expected to perturb a GyrA-GyrA dimer interface allowed nalidixic acid to fragment chromosomes and kill cells in the absence of protein synthesis; moreover, it made a non-inducible lexA mutant hypersusceptible to nalidixic acid, a property restricted to fluoroquinolones with wild-type cells. The GyrA variation also facilitated immunoprecipitation of DNA fragments by GyrA antiserum following nalidixic acid treatment of cells. The ability of changes in both gyrase and quinolone structure to enhance protein synthesis-independent lethality and chromosome fragmentation is explained by drug-mediated destabilization of gyrase-DNA complexes. Instability of type II topoisomerase-DNA complexes may be a general phenomenon that can be exploited to kill cells.

Amino Acid Substitution↗

PubMed2004

[Antimicrobial drug resistance in non-typhi Salmonellae in Castilla y Leon].

We studied the antibiotic susceptibility of 309 Salmonella isolates obtained from three hospitals serving the provinces of Salamanca, Avila and Zamora in the region of Castilla y Leon (mid-west Spain). The susceptibility to 18 antibiotics was studied using the agar dilution method, according to NCCLS guidelines, and the most common multiresistance phenotypes were determined for each province. We observed clear susceptibility differences between the two main serotypes found, S. enteritidis and S. typhimurium. Seventy percent of S. typhimurium were resistant to amoxicillin. In 44% of these isolates, amoxicillin resistance was associated with resistance to streptomycin, sulfonamides, tetracyclines and chloramphenicol. S. enteritidis was susceptible to most antibiotics tested; amoxicillin resistance was observed in 23.3%, and nalidixic acid resistance in 49.6%. Resistance to nalidixic acid was higher in S. enteritidis than in any other serotypes. According to NCCLS breakpoints, no strain was resistant to fluoroquinolones. However, according to MENSURA criteria, 9% of S. typhimurium isolates were resistant to ciprofloxacin. Resistance to cotrimazole and gentamicin was less than 10% for all the serotypes tested. The results indicate that S. typhimurium showed greater resistance and a high multidrug resistance rate. Conversely, S. enteritidis showed high resistance only to amoxicillin and nalidixic acid, though in most cases there was no correlation between this resistance and reduced susceptibility to fluoroquinolones.

Anti-Bacterial Agents↗

PubMed2001

LuxArray, a high-density, genomewide transcription analysis of Escherichia coli using bioluminescent reporter strains.

A sequenced collection of plasmid-borne random fusions of Escherichia coli DNA to a Photorhabdus luminescens luxCDABE reporter was used as a starting point to select a set of 689 nonredundant functional gene fusions. This group, called LuxArray 1.0, represented 27% of the predicted transcriptional units in E. coli. High-density printing of the LuxArray 1.0 reporter strains to membranes on agar plates was used for simultaneous reporter gene assays of gene expression. The cellular response to nalidixic acid perturbation was analyzed using this format. As expected, fusions to promoters of LexA-controlled SOS-responsive genes dinG, dinB, uvrA, and ydjM were found to be upregulated in the presence of nalidixic acid. In addition, six fusions to genes not previously known to be induced by nalidixic acid were also reproducibly upregulated. The responses of two of these, fusions to oraA and yigN, were induced in a LexA-dependent manner by both nalidixic acid and mitomycin C, identifying these as members of the LexA regulon. The responses of the other four were neither induced by mitomycin C nor dependent on lexA function. Thus, the promoters of ycgH, intG, rihC, and a putative operon consisting of lpxA, lpxB, rnhB, and dnaE were not generally DNA damage responsive and represent a more specific response to nalidixic acid. These results demonstrate that cellular arrays of reporter gene fusions are an important alternative to DNA arrays for genomewide transcriptional analyses.

Artificial Gene Fusion↗

PubMed1995

Evaluation of the API-campy system in the biochemical identification of hippurate negative campylobacter strains isolated from faeces.

The aim was to evaluate the efficacy of the API-Campy system in the biochemical identification of 62 hippurate negative campylobacter strains isolated from the faeces. The strains were identified manually as 34 nalidixic acid susceptible C coli (NAS), 20 nalidixic acid resistant C coli (NAR), and eight C lari. The 34 strains of NAS C coli were identified as such by the API-Campy system. Of the 20 strains of NAR C coli, 15 (75%) were correctly identified by the commercial system. None of the five NAR C coli strains which were also erythromycin resistant was identified as such by the system. The eight C lari strains could not be identified by the API-Campy system because the bionumber obtained does not exist in the database of the computer system. The API-Campy system could be very useful for the identification of NAS C coli. However, failure to allow for a higher percentage of resistance to nalidixic acid in this species does not permit good identification of NAR strains. More important discrepancies are observed in C lari strains. In order to improve the identification of NAR C coli and C lari stains, it is advisable to include, or recommend as complementary, the indoxyl acetate hydrolysis test.

Bacterial Typing Techniques↗

PubMed1995

Protective effect of fluoroquinolones on dapsone induced erythrolysis.

Various quinolones have varied effects on the preservative activity of blood cells. Nalidixic acid causes hemolysis in G-6PD deficient patients where as ofloxacin has been found to possess preservative action of WBCs. The present study was undertaken to see the effect of various fluoroquinolones on RBC membrane. The effect of quinolones like ciprofloxacin, ofloxacin and norfloxacin and nalidixic acid in the dose of 5 micrograms/ml was studied on dapsone induced, in vitro hemolysis of rabbit RBC, using the osmotic fragility test. The mean corpusular fragility (MCF) with various agents were as follows: (mean +/- SE) saline; 5.23 +/- 0.21; dapsone, 6.57 +/- 0.23; ofloxacin, 3.81 +/- 0.13; ofloxacin and dapsone, 5.13 +/- 0.11; nalidixic acid, 6.28 +/- 0.16; nalidixic acid and dapsone, 6.65 +/- 0.13; ciprofloxacin, 3.52 +/- 0.22; ciprofloxacin and dapsone, 4.80 +/- 0.2; norfloxacin, 1.97 +/- 0.23; norfloxacin and dapsone, 4.27 +/- 0.20. The MCF data and shift of the osmotic fragility curves (to the left) show that dapsone induced erythrolysis is significantly protected by ciprofloxacin, ofloxacin and norfloxacin but not by nalidixic acid.

Animals↗

PubMed2000

A bioassay evaluation of the urinary antibacterial efficacy of low dose prophylactic antibiotics in children with vesicoureteral reflux.

PURPOSE: We evaluated by means of a bioassay the efficacy of 4 different antibiotics administered in a prophylactic dose to children with vesicoureteral reflux. MATERIALS AND METHODS: A total of 159 urine samples from 53 children taking prophylactic antibiotics with proved vesicoureteral reflux were tested. The children were divided into 4 groups according to the antibiotic given, which included nalidixic acid, cephalexin, cotrimoxazole and cefixime. Urine samples were collected in the morning, at noon and in the evening, and each sample was bioassayed for growth inhibition of a standard Escherichia coli. The urine volume used was specifically determined for each antibiotic, and growth inhibition by this specific volume was equivalent to that produced by standard diffusion disks. In addition, the specific gravity, which reflected urinary concentration of each sample, was measured. RESULTS: Mean patient age plus or minus standard deviation of the 4 groups was 53 +/- 41 for nalidixic acid, 23 +/- 34 for cephalexin, 55 +/- 35 for cotrimoxazole and 47 +/- 35 months for cefixime, respectively. In children less than 2 years old specific gravity was higher in the morning (1.021 +/- 0.0006 versus 1.0008 +/- 0.0004 at 8 a.m. and 2 p. m., respectively, p <0.05). In contrast, in children older than 4 years the specific gravity was higher in the afternoon and evening hours (1.019 +/- 0.003 versus 1.007 +/- 0.003 at 2 p.m. and 8 a.m., respectively, p <0.05). The percentage of patients who demonstrated growth inhibition in all 3 samples of the test day was 7%, 6%, 69% and 44% for nalidixic acid, cephalexin, cotrimoxazole and cefixime, respectively (p <0.001 for cotrimoxazole and cefixime versus nalidixic acid and cephalexin. Divided into morning, noon and evening, the percentage of samples that demonstrated growth inhibition was 85.7%, 21.4% and 7.1% for nalidixic acid, 37.5%, 12. 5% and 6.3% for cephalexin, 100%, 92.3% and 76.9% for cotrimoxazole and 100%, 77.7% and 55.5% for cefixime, respectively. A direct correlation was found between specific gravity and growth inhibition (r = 0.55, p <0.001). CONCLUSIONS: Urine concentration during the day is dependent on age with older children having more concentrated urine in the latter part of the day. Growth inhibition is enhanced by concentrated urine. Compared to nalidixic acid and cephalexin, cotrimoxazole and cefixime produce a sustained bactericidal effect for about 60% of a 24-hour day due to the longer half-life.

Anti-Bacterial Agents↗

PubMed1991

Transformation of Neisseria gonorrhoeae: physical requirements of the transforming DNA.

The 1600-bp (base pair) fragment encoding a portion of the nalidixic acid resistant DNA gyrase, subunit B, was characterized to determine what parameters effect transformation in the gonococcus. When this DNA (pSY2) was isolated from Escherichia coli, it was able to transform a variety of gonococcal strains to resistance to nalidixic acid via DNA-mediated transformation, irrespective of their restriction-modification phenotype. Nalidixic acid resistant transformants contained no plasmid DNA sequences that corresponded to the vector, as measured by plasmid screening procedures and colony hybridization techniques. Supercoiled and linear DNA transformed the gonococcus at the same efficiency. DNA fragments as small as 615 bp were able to transform the gonococcus. The presence of a 10-bp uptake sequence enhanced a DNA fragment's ability to transform the gonococcus by four orders of magnitude. When the fragment encoding the nalidixic acid resistant DNA gyrase was subcloned into M13mp18, both the replicative form and the single-stranded form of the phage were able to transform the gonococcus to nalidixic acid resistance.

Cloning, Molecular↗

PubMed1999

The damage-inducible (din) genes of Escherichia coli are induced by various genotoxins in a different way.

The SOS response of Escherichia coli strains carrying the lacZ gene fused to the polB (dinA), dinB or dinD gene were investigated after treatment with several chemical agents and gamma-radiation. The induction levels of polB::lacZ reached levels between 4.0- and 9.0-fold 120 min after treatment with nalidixic acid, H2O2 or ethanol. Pentachlorophenol did not significantly induce any din genes. gamma-Irradiation is not an inducer of polB and ethanol failed to induce dinB::lacZ and dinD::lacZ. Following irradiation with a dose of 10 Gy the responses of dinB and dinD were induced about 2.5-3.0-fold above non-irradiated dinB and dinD. We found that the responses of din::lacZ fusion genes to these genotoxins are induced in a dose-dependent manner. The polB gene showed antagonistic responses to the simultaneous treatment of nalidixic acid and H2O2 or nalidixic acid and ethanol. In addition, dinB and dinD in the presence of both nalidixic acid and H2O2 at the same time showed no synergistic responses.

Bacterial Proteins↗

PubMed1988

SOS independent survival against mitomycin C induced lethality in a rifampicin-nalidixic acid-resistant mutant of Escherichia coli.

A combination of specific rifampicin-resistant (rpoB87) and nalidixic acid-resistant (gyrA87) mutations results in a marked increase in the survival of Escherichia coli against mitomycin C-induced lethality in mutants defective for SOS induction and excision repair. Although the response does not seem to be obligatorily dependent upon the RecA protein, the efficiency is markedly increased in its presence, even in a conventionally inactive form. This response is not elicited against lethality due to ultraviolet radiation or N-methyl-N' -nitro-N-nitrosoguanidine exposure. The combination of rpoB87 and gyrA87 mutations also greatly alleviates post-mitomycin C degradation of DNA under SOS non-inducible conditions. It is proposed that the rpoB subunit of RNA polymerase and gyrA subunit of DNA gyrase could participate in the repair of certain types of DNA damage, such as cross-links, in a mode independent of SOS-regulated excision repair and post-replication repair.

DNA Repair↗

PubMed1992

Nalidixic acid-resistant V79 cells with reduced DNA topoisomerase II activity and amplification prone phenotype.

Spontaneously nalidixic acid-resistant lines (NAr lines) were selected from a V79 Chinese hamster cell line and phenotypically characterized. NAr lines showed an increased doubling time, a higher number of spontaneous SCE, and more interestingly, decreased DNA topoisomerase II activity. These lines were also cross-resistant to the eukaryotic topoisomerase II inhibitors etoposide and adriamycin, but showed the same level of sensitivity as the parental line to the DNA topoisomerase I inhibitor camptothecin. NAr lines were cross-resistant to other drugs, such as PALA, MTX and MPA, resistance to which has been shown to arise by amplification of the target genes. This last feature, together with enhanced cross-resistance to PALA and MTX when employed simultaneously, suggests that NAr lines have an 'amplification prone' phenotype. From these results the decreased activity of topoisomerase II seems to be involved in the generation of amplified sequences possibly by affecting recombinational events underlying gene amplification.

Animals↗