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PubMed1993

Novobiocin forms cation-permeable ion channels in rat fetal distal lung epithelium.

The antibiotic novobiocin has been previously reported to increase Na+ transport in frog skin, presumably by attenuation of Na+ self-inhibition of Na+ channels. To determine whether novobiocin had similar effects and utilized a similar mechanism in mammalian Na(+)-transporting tissues, we studied its effect on ion transport by primary cultures of fetal distal lung epithelium (FDLE) cultured from 20-day gestationally aged rats (term = 22 days). Novobiocin (10 mM) increased short-circuit current and markedly decreased the resistance in FDLE monolayers mounted in Ussing chambers. Fura-2 single-cell studies showed that novobiocin increased intracellular Ca2+ concentration and that this resulted from extracellular sources. Nystatin-perforated patch-clamp techniques demonstrated that novobiocin increased nonrectifying cation whole cell currents without inducing detectable anion currents. Novobiocin created nonrectifying monovalent cation-selective channels in lipid bilayers. These studies demonstrated that novobiocin affects the bioelectric properties of Na+ transporting lung epithelium and that this likely occurs by the formation of ion-permeant channels in their lipid membranes.

Animals↗

PubMed1997

The activity of a combination of penicillin and novobiocin against bovine mastitis pathogens: development of a disk diffusion test.

The combination of penicillin and novobiocin is currently available for the treatment of bovine mastitis, but methods are not available for susceptibility testing of the combination by veterinary diagnostic laboratories. The minimum inhibitory concentration (MIC) and disk diffusion data were determined for penicillin, novobiocin, and a combination of the two in a 1:2 ratio for 225 staphylococcal, streptococcal, and Gram-negative isolates from bovine intramammary infections. Based on the drug concentrations in milk following infusion, linear regression analysis, and error rate bounding, the interpretive zone diameters selected were < or = 16 mm for resistant isolates and > or 17 mm for susceptible isolates with a disk containing 10 U of penicillin and 30 micrograms of novobiocin. Additionally, MIC breakpoints of < or = 2 micrograms/ml of penicillin and 4 micrograms/ml of novobiocin were selected to categorize isolates as susceptible and > or = 4 micrograms/ml of penicillin and 8 micrograms/ml of novobiocin were selected to categorize isolates as resistant. The MIC and disk diffusion results, as well as studies to monitor bacterial killing by antimicrobial agents over time, indicated that the combination of penicillin and novobiocin in a 1:2 ratio was more active than were the individual drugs. Kinetics of the kill curves with the penicillin and novobiocin combination (1:2 ratio) showed that the combination was bactericidal for Staphylococcus aureus and Staphylococcus xylosus.

Animals↗

PubMed1999

Enhancement of the activity of novobiocin against Escherichia coli by lactoferrin.

The activity of novobiocin against Escherichia coli ATCC 25922 and three E. coli strains that were isolated from cases of bovine mastitis was determined in timekill studies in the presence of bovine lactoferrin. Lactoferrin alone did not affect the growth of any of the strains of E. coli. A combination of 1.0 mg/ml of lactoferrin and novobiocin at 1/16x minimum inhibitory concentration (MIC) was bactericidal for E. coli ATCC 25922. When the concentration was increased to 3.0 mg/ml of lactoferrin, novobiocin was bactericidal at 1/64x MIC. Among the mastitis strains tested, 6789 and 6806 were more susceptible to killing by novobiocin than was strain 6800. Strains 6789 and 6806 were killed when treated with novobiocin concentrations of 2, 1/2, and 1/4x MIC. When these strains were also treated with lactoferrin at 3.0 mg/ml, there was a bacteriostatic effect at novobiocin concentrations of 1/8 and 1/16x MIC for strains 6789 and 6800. Strain 6806 appeared to be more susceptible to the combination of lactoferrin and novobiocin as was evidenced by a bactericidal effect over the 24-h testing period. The combination treatment with cephapirin and lactoferrin showed that there was a synergistic bactericidal effect against all of the E. coli strains tested. These studies indicate that lactoferrin can potentiate the activity of antibiotics against Gram-negative bacteria.

Animals↗

PubMed2000

Novobiocin-induced VP-16 accumulation and MRP expression in human leukemia and ovarian carcinoma cells.

We have previously reported that novobiocin potentiates the cytotoxic activity of etoposide (VP-16) and teniposide (VM-26) in a number of experimental tumor cell lines by inhibition of the efflux of the epipodophyllotoxins by an ATP-requiring transporter. In leukemia cells from 12/19 patients and in ovarian carcinoma cells from 2/4 patients, novobiocin, in a concentration range of 150-1000 microM, increased the intracellular accumulation of VP-16 by 30-250% by inhibiting its efflux. Novobiocin did not significantly increase the intracellular concentration of VP-16 in human mononuclear bone marrow cells from two individuals with normal bone marrow, suggesting that it might be possible to selectively modulate the intracellular accumulation of the epipodophyllotoxin in tumor cells relative to normal hematopoietic tissue. Previous findings from our laboratory have provided evidence that the membrane transporter for VP-16 which is inhibited by novobiocin is distinct from the P-glycoprotein. The expression of MRP, measured by immunoblotting, was variable in novobiocin-responsive and non-responsive leukemia cells, indicating that no direct relationship existed between the modulatory activity of novobiocin on the transport of VP-16 and the expression of the MRP gene. The findings indicate that the novobiocin-sensitive VP-16 transporter is (i) present in high frequency in leukemia and ovarian carcinoma cells, and (ii) probably not the P-glycoprotein or MRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1990

Activation of internucleosomal DNA cleavage in human CEM lymphocytes by glucocorticoid and novobiocin. Evidence for a non-Ca2(+)-requiring mechanism(s).

Internucleosomal DNA cleavage is the key molecular event of the cytolytic phase of glucocorticoid-induced lymphocytolysis. We find that novobiocin, the topoisomerase II inhibitor, is a potent inducer of in vivo internucleosomal DNA cleavage in human CEM lymphocytes. This in vivo effect is very rapid, time- and dose-dependent, requires cellular integrity, and does not require de novo protein synthesis. Recently our data (Alnemri, E. S., and Litwack, G. (1989) J. Biol. Chem. 264, 4104-4111) suggested that activation of DNA cleavage in CEM-C7 lymphocytes by glucocorticoids is independent of calcium uptake. Similarly, the novobiocin effect is also independent of calcium uptake and does not occur in isolated CEM nuclei or in CEM cells treated previously with the divalent cation ionophore A23187. Internucleosomal DNA cleavage induced by novobiocin or glucocorticoid generates blunt-ended double-stranded DNA fragments possessing 3'-hydroxyls and 5'-phosphates. As demonstrated by gel retardation analysis and DNase I footprinting, novobiocin causes the disruption and unfolding of an in vitro reconstituted mononucleosome so that it becomes more susceptible to DNase I cleavage. Our data suggest that 1) novobiocin rapid activation of internucleosomal DNA cleavage and chromatin changes in CEM lymphocytes are molecular features of apoptosis or programmed cell death. 2) CEM lymphocytes apparently do not express a Ca2(+)-dependent endonuclease. 3) The mechanism(s) of glucocorticoid or novobiocin-induced DNA cleavage in CEM lymphocytes involves activation of a constitutive non Ca2(+)-dependent endonuclease. We propose that the majority of nuclear chromatin is maintained in a highly compact and charge-neutralized state and that disruption of this highly ordered structure, directly by novobiocin or indirectly by glucocorticoid, may lead to the exposure and unmasking of internucleosomal linker DNA regions which are substrates for a constitutive non-Ca2(+)-dependent endonuclease.

Amsacrine↗

PubMed1993

Studies on mutational cross-resistance between ciprofloxacin, novobiocin and coumermycin in Escherichia coli and Staphylococcus warneri.

Nalidixic acid resistant mutants of Escherichia coli KL16 were tested against ciprofloxacin, coumermycin and novobiocin. The mutants gyrA, nalB and nal-24 were more resistant than KL16 to ciprofloxacin, whereas the nal-31 strain was hypersensitive. Only the nalB mutant was more resistant to novobiocin than KL16, but gyrA, nal-31 and nal-24 mutants were more sensitive to coumermycin than KL16. Newly-isolated novobiocin-resistant mutants of KL16 were not cross-resistant to coumermycin or ciprofloxacin. Some coumermycin-resistant mutants were cross-resistant to novobiocin but not ciprofloxacin, whereas mutants resistant to novobiocin and ciprofloxacin were isolated at higher coumermycin concentrations. Two types of Staphylococcus warneri mutant were isolated on media containing novobiocin or coumermycin. Each was resistant to both coumarins, but one was highly resistant to novobiocin and the other to coumermycin. High level resistance to both coumarins was unstable. E. coli mutants differed in susceptibility to bactericidal concentrations of ciprofloxacin, and S. warneri mutants behaved similarly. These results suggest the modes of action of the coumarins are not identical.

Aminocoumarins↗

PubMed1988

Na transport stimulation by novobiocin: intracellular ion concentrations and membrane potential.

Microelectrodes and electron microprobe analysis were employed to study the effect of novobiocin on membrane potential and intracellular electrolyte concentrations in the frog skin epithelium. In both species investigated (Rana esculenta and Rana temporaria), novobiocin (1 mM, outer bath) caused a stimulation of transepithelial Na transport, a depolarization of apical membrane potential, a fall in the apical fractional resistance, and an increase in the intracellular Na concentration. The rise in the Na concentration was accompanied by an equivalent fall in the K concentration. All effects of novobiocin were fully reversible by subsequent application of amiloride. The depolarization as well as the Na increase suggests that the natriferic effect of novobiocin is due to a stimulation of the apical Na influx. Combining both measurements it was possible to calculate the effect of novobiocin on the Na permeability of the apical membrane directly. In Rana esculenta novobiocin increased the permeability from 4.5 to 23.2 nm/s. In Rana temporaria the increase was significantly smaller, from 8.7 to 16.9 nm/s. The transport rate as measured by the short-circuit current showed a non-linear dependence on the apical Na permeability. In the range of transport rates normally encountered, however, the current was a linear function of the Na permeability consistent with the view that the apical membrane is rate-limiting in transepithelial Na transport.

Amiloride↗

PubMedDate not supplied

Serum inhibitory and bactericidal activity against methicillin-resistant Staphylococcus aureus in volunteers receiving novobiocin and rifampin alone and in combination.

The combination of novobiocin and rifampin is effective in eliminating colonization due to methicillin-resistant Staphylococcus aureus (MRSA) and in treating experimental MRSA soft tissue infections. To evaluate novobiocin, rifampin, and the combination of the two agents for potential oral therapy in patients with MRSA infections, we measured the serum inhibitory and bactericidal activity from four volunteers against 20 MRSA strains obtained from seven different institutions. When Stratton-Reller methods employing 50% human serum were used to perform the assay, rifampin produced peak mean serum inhibitory titers of 1:40, whereas novobiocin alone produced essentially no inhibitory activity. The combination of novobiocin plus rifampin had similar inhibitory activity as rifampin alone. The bactericidal titers produced by the three regimens were significantly less than inhibitory titers. In additional studies, involving serum from five volunteers tested against seven representative strains, peak mean serum inhibitory activity of novobiocin was 1:232 when Mueller-Hinton broth was used as the diluent compared with < 1:2 when 50% human serum was used. We conclude that despite the high degree of activity of novobiocin in broth, its activity against MRSA in serum is minimal, probably related to the high degree of protein binding of that antibiotic.

Administration, Oral↗

PubMed2000

Novobiocin in combination with high-dose chemotherapy for the treatment of advanced breast cancer: a phase 2 study.

We conducted the first phase 2 and pharmacologic study to evaluate the combination of novobiocin (a coumeromycin antibiotic that has been shown to augment alkylating agent cytotoxicity in experimental models) and high-dose cyclophosphamide and thiotepa followed by autologous marrow support in women with chemosensitive advanced breast cancer. Its aims were (1) to determine progression-free survival (PFS) and overall survival (OS), (2) to evaluate the pharmacokinetics of cyclophosphamide and thiotepa, and (3) to measure the ability of novobiocin to reverse alkylator drug resistance in vitro. Forty-one women with chemotherapy-responsive advanced breast cancer received cyclophosphamide (4 g/m2) for peripheral blood stem cell mobilization (treatment 1) followed by high-dose cyclophosphamide (1.5 g/m2 per day for 4 days), thiotepa (200 mg/m2 per day for 4 days), and novobiocin (4 g/day orally for 7 days) (treatment 2) and autologous marrow support. The median PFS was 10 months (range, 0.2-70.6 months) and OS, 21.5 months (range, 0.2-70.6 months). There was no statistically significant relationship between PFS or OS and area-under-the-curve values of cyclophosphamide, thiotepa, or 4-hydroxycyclophosphamide. Patient plasma samples (n = 12) obtained during novobiocin therapy were able to reverse alkylator drug resistance in an in vitro colony-forming assay. Correlative laboratory studies in an in vitro model system demonstrated that patient plasma after novobiocin treatment resulted in the magnitude of resistance reversal that had been predicted by prior preclinical experiments. Clinically, however, this activity of novobiocin did not translate into a substantial increase in PFS or OS compared with historical controls treated with high-dose alkylator therapy alone.

Adult↗

PubMed1986

Increase in the frequency of gamma-ray induced chromosomal aberrations in mammalian cells by post-treatment with novobiocin.

The effect of novobiocin (an inhibitor of DNA topoisomerase and polymerase) on the frequency of chromosomal aberrations was examined in Chinese hamster V79 cells irradiated with gamma-rays in the plateau phase of growth and subcultured in the presence of novobiocin until the first mitosis after irradiation. Novobiocin alone affected cell survival, DNA synthesis and the mitotic frequency of unirradiated cells in a dose-dependent manner, without causing any significant increase in the frequency of chromosome- or chromatid-type aberrations. The frequency of chromosome-type aberrations induced by gamma-radiation was not influenced by novobiocin at 200 microM, but the frequency of chromosome deletions (but not rings and dicentrics) showed a two-fold increase when 300 microM novobiocin was present. Irradiation produced a low level of chromatid-type aberrations and post-treatment with novobiocin at concentrations greater than 100 microM significantly increased the frequency of chromatid gaps and breaks. The results support the idea that different radiation-induced lesions lead to chromosome- as opposed to chromatid-type aberrations.

Animals↗

PubMed1982

Studies on the inhibition of repair of ultraviolet- and methyl methanesulfonate-induced damage in the DNA of human fibroblasts by novobiocin.

The antibiotic novobiocin is shown to alter the sedimentation properties of human cellular DNA in alkaline sucrose. This alteration is at least partially due to increased DNA-protein binding in the cell in the presence of novobiocin. Pyrimidine dimer analysis and repair replication studies support previous reports that novobiocin inhibits repair of UV damage in human cells but we find this block to be shortlived. It is also shown that novobiocin is ineffective at blocking "long-patch" repair induced by methyl methanesulfonate as measured both by CsCl density centrifugation and the ara-C inhibition technique. However, the accumulation of breaks in MMS-treated cellular DNA in the presence of novobiocin suggests that some "short-patch" alkylation repair may be inhibited by the antibiotic. These findings are discussed in light of the proposal that novobiocin may inhibit a DNA gyrase-like activity in human as in bacterial cells.

Cell Line↗

PubMed1987

Novobiocin interferes with the binding of transcription factors TFIIIA and TFIIIC to the promoters of class III genes.

Novobiocin has been shown to inhibit class III gene transcription from both chromatin and non-chromatin templates. Since novobiocin is a well characterized inhibitor of type II DNA topoisomerases, it has been postulated that a gyrase activity is necessary for transcription. Using DNase I footprinting, we show here that novobiocin inhibits the specific binding of polymerase III transcription factors TFIIIA and TFIIIC to the promoters of the 5S RNA and VA RNA genes, respectively. Concentrations of novobiocin employed were comparable to those necessary to inhibit HeLa topoisomerase II. In vitro transcription assays, performed under equivalent conditions, demonstrated that similar novobiocin concentrations were necessary for transcription inhibition. These results strongly suggest that novobiocin interferes with transcription by inhibiting specific protein-DNA interactions.

Adenoviruses, Human↗

PubMed1987

Novobiocin inhibits initiation of RNA polymerase II-directed transcription of the mouse metallothionein-I gene independent of its effect on DNA topoisomerase II.

The requirement for ATP hydrolysis in the initiation of RNA polymerase II (Pol II)-directed transcription and the relationship between ATP and novobiocin action led us to investigate whether novobiocin could inhibit transcription of the mouse metallothionein-I (MT-I) gene. Novobiocin inhibited the MT-I gene transcription in a fractionated rat hepatoma nuclear extract in a dose-dependent manner by direct interaction with a nuclear factor(s). This interaction prevented formation of stable preinitiation complexes but did not affect elongation of MT-I mRNA. Preincubation of the nuclear extract with ATP prevented the action of novobiocin on MT-I gene transcription. Although novobiocin is known to inhibit DNA topoisomerase II, VM-26, a specific inhibitor of this enzyme had no effect on the transcription. These results indicate that novobiocin blocks the Pol II-directed transcription by inhibiting formation of preinitiation complexes at an ATP-dependent step.

Animals↗

PubMed1987

Novobiocin inhibits interactions required for yeast TFIIIB sequestration during stable transcription complex formation in vitro.

Novobiocin concentrations normally used to inhibit a putative eukaryotic DNA gyrase have been found to inhibit transcription of a yeast 5S rRNA gene using an in vitro yeast transcription system. Purified RNA polymerase III and three yeast transcription factors (chromatographically separated, partially purified and free of any detectable gyrase activity) were used. Novobiocin prevents specific transcription if added to the in vitro system immediately prior to the addition of transcription factors and RNA polymerase. If a stable transcription factor complex is allowed to form prior to the addition of novobiocin, concentrations of novobiocin as high as 1000 micrograms/ml have no effect on in vitro transcription. Transcription factors TFIIIA and TFIIIC are able to be stably sequestered onto 5SrDNA-cellulose, but factor TFIIIB is not able to associate with the 5SrDNA-TFIIIA-TFIIIC complex in the presence of novobiocin. Although novobiocin is able to precipitate other basic proteins, it does not appear to precipitate any of these class III gene transcription factors, but instead appears to act by disrupting specific factor-factor interactions.

Genes, Fungal↗

PubMed1993

Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen in hospitals. Current antimicrobial regimens for eradicating colonizing strains are not well defined and are often complicated by the emergence of resistance. The combination of novobiocin plus rifampin in vitro and in vivo was found to prevent the emergence of resistant populations of initially susceptible strains of MRSA, particularly resistance to rifampin. We therefore studied, in a randomized, double-blind, multicenter comparative trial, the combination of novobiocin plus rifampin versus trimethoprim-sulfamethoxazole (T/S) plus rifampin in order to determine the efficacy of each regimen in eradicating MRSA colonization and to further characterize the host factors involved in the response to this antimicrobial therapy. Among the 126 individuals enrolled in the study, 94 (80 patients; 14 hospital personnel) were evaluable. Among the 94 evaluable subjects, no significant demographic or medical differences existed between the two treatment groups. Successful clearance of the colonizing MRSA strains was achieved in 30 of 45 (67%) subjects receiving novobiocin plus rifampin, whereas successful clearance was achieved in 26 of 49 (53%) subjects treated with T/S plus rifampin (P = 0.18). The emergence of resistance to rifampin developed more frequently in 14% (7 of 49) of subjects treated with T/S plus rifampin than in 2% (1 of 45) of subjects treated with novobiocin plus rifampin (P = 0.04). Restriction endonuclease studies of large plasmid DNA demonstrated that the same strain was present at pretherapy and posttherapy in most refractory cases (24 of 29 [83%] subjects). Among the 56 successfully treated subjects, clearance of MRSA was age dependent: 29 of 36 (80%) subjects in the 18- to 49-year-old age group, 19 of 35 (54%) subjects in the 50- to 69-year-old age group, and 8 of 23 (35%) in the 70- to 94-year-old age group (P < 0.01). Clearance was also site dependent; culture-positive samples from wounds were related to a successful outcome in only 22 (48%) of 46 subjects, whereas culture-positive samples from sites other than wounds (e.g., nares, rectum, and sputum) were associated with a success rate of 34 of 48 (71%) subjects (P = 0.02). Foreign bodies in wounds did not prevent the eradication of MRSA by either regimen. T/S plus rifampin was less effective in clearing both pressure and other wounds, whereas novobiocin plus rifampin was equally effective in clearing both pressure and other wounds. There were no significant differences in toxicity between the two regimens. Thus, the combination of novobiocin plus rifampin, in comparison with T/S plus rifampin, was more effective in preventing the emergence of resistance to rifampin and demonstrated a trend toward greater activity in clearing the MRSA carrier state. The response to either combination depended on host factors, particularly age and the site of MRSA colonization.

Adolescent↗

PubMed1973

Effect of novobiocin and its combination with tetracycline, chloramphenicol, erythromycin, and lincomycin on the microbial generation of Escherichia coli.

Inhibition of the steady-state generation of Escherichia coli by the bacteriostatic antibiotic novobiocin is linearly related to drug concentration in the range of 0 to 30 mug/ml. Increased cell sizes result because the drug inhibits cell division. The generation rate dependence on drug concentration depends on the nonionized fraction of novobiocin and is invariant with inoculum size or medium composition. However, the antibacterial activity of novobiocin decreases as the concentration of nutrients and Mg(2+) increases, although the inhibitory action of novobiocin on generation rate remains unchanged for concentrations of Mg(2+) above 8.1 x 10(-4) M. Novobiocin is synergistic in combinations with tetracycline in broth, but not when the Mg(2+) was maintained at 4.05 x 10(-3) M. Combinations of novobiocin with the 50S ribosomal subunit inhibitors chloramphenicol, erythromycin, or lincomycin are antagonistic, and the degree of growth inhibition is determined only by that component of the binary combination that would have the greater potency if it were acting alone.

Cell Division↗

PubMed2000

Identification of the novobiocin biosynthetic gene cluster of Streptomyces spheroides NCIB 11891.

The novobiocin biosynthetic gene cluster from Streptomyces spheroides NCIB 11891 was cloned by using homologous deoxynucleoside diphosphate (dNDP)-glucose 4,6-dehydratase gene fragments as probes. Double-stranded sequencing of 25.6 kb revealed the presence of 23 putative open reading frames (ORFs), including the gene for novobiocin resistance, gyrB(r), and at least 11 further ORFs to which a possible role in novobiocin biosynthesis could be assigned. An insertional inactivation experiment with a dNDP-glucose 4, 6-dehydratase fragment resulted in abolishment of novobiocin production, since biosynthesis of the deoxysugar moiety of novobiocin was blocked. Heterologous expression of a key enzyme of novobiocin biosynthesis, i.e., novobiocic acid synthetase, in Streptomyces lividans TK24 further confirmed the involvement of the analyzed genes in the biosynthesis of the antibiotic.

Amide Synthases↗

PubMed1979

Specific inhibition of outgrowth of Bacillus subtilis spores by novobiocin.

Spores of a Bacillus subtilis mutant temperature sensitive in deoxyribonucleic acid (DNA) replication proceeded through outgrowth at the nonpermissive temperature to the same extent as the wild-type parent spores. In contrast, the DNA synthesis inhibitor novobiocin completely prevented spore outgrowth while displaying a marginal effect on logarithmic growth during one generation time. Inhibition of outgrowth by novobiocin occurred in the absence of DNA replication, as demonstrated in an experiment with spores of the temperature-sensitive DNA synthesis mutant at the restrictive temperature. Novobiocin inhibited the initial rate of ribonucleic acid synthesis to the same extent in germinated spores and in exponentially growing cells. A novobiocin-resistant mutant underwent normal outgrowth in the presence of novobiocin. Therefore, novobiocin inhibition was independent of its effect on chromosome replication per se.

Bacillus subtilis↗