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PubMed1998

Neomycin B inhibits splicing of the td intron indirectly by interfering with translation and enhances missplicing in vivo.

The aminoglycoside antibiotic neomycin B inhibits translation in prokaryotes and interferes with RNA-protein interactions in HIV both in vivo and in vitro. Hitherto, inhibition of ribozyme catalysis has only been observed in vitro. We therefore monitored the activity of neomycin B and several other aminoglycoside antibiotics on splicing of the T4 phage thymidylate synthase (td) intron in vivo. All antibiotics tested inhibited splicing, even chloramphenicol, which does not inhibit splicing in vitro. Splicing of the td intron in vivo requires translation for proper folding of the pre-mRNA. In the absence of translation, two interactions between sequences in the upstream exon and the 5' and 3' splice sites trap the pre-mRNA in splicing-incompetent conformations. Their disruption by mutations rendered splicing less dependent on translation and also less sensitive to neomycin B. Intron splicing was affected by neither neomycin B nor gentamicin in Escherichia coli strains carrying antibiotic-resistance genes that modify the ribosomal RNA. Taken together, this demonstrates that in vivo splicing of td intron is not directly inhibited by aminoglycosides, but rather indirectly by their interference with translation. This was further confirmed by assaying splicing of the Tetrahymena group I intron, which is inserted in the E. coli 23 S rRNA and, thus, not translated. Furthermore, neomycin B, paromomycin, and streptomycin enhanced missplicing in antibiotic-sensitive strains. Missplicing is caused by an alternative structural element containing a cryptic 5' splice site, which serves as a substrate for the ribozyme. Our results demonstrate that aminoglycoside antibiotics display different effects on ribozymes in vivo and in vitro.

Animals↗

PubMed2006

Dissection of aminoglycoside-enzyme interactions: a calorimetric and NMR study of neomycin B binding to the aminoglycoside phosphotransferase(3')-IIIa.

In this work, for the first time, we report pKa values of the amino functions in a target-bound aminoglycoside antibiotic, which permitted dissection of the thermodynamic properties of an enzyme-aminoglycoside complex. Uniformly enriched 15N-neomycin was isolated from cultures of Streptomyces fradiae and used to study its binding to the aminoglycoside phosphotransferase(3')-IIIa (APH) by 15N NMR spectroscopy. 15N NMR studies showed that binding of neomycin to APH causes upshifts of approximately 1 pKa unit for the amines N2' and N2' '' while N6' experienced a 0.3 pKa unit shift. The pKa of N6' '' remained unaltered, and resonances of N1 and N3 showed significant broadening upon binding to the enzyme. The binding-linked protonation and pH dependence of the association constant (Kb) for the enzyme-aminoglycoside complex was determined by isothermal titration calorimetry. The enthalpy of binding became more favorable (negative) with increasing pH. At high pH, binding-linked protonation was attributable mostly to the amino functions of neomycin; however, at neutral pH, functional groups of the enzyme, possibly remote from the active site, also underwent protonation/deprotonation upon formation of the binary enzyme-neomycin complex. The Kb for the enzyme-neomycin complex showed a complicated dependence on pH, indicating that multiple interactions may affect the affinity of the ligand to the enzyme and altered conditions, such as pH, may favor one or another. This work highlights the importance of determining thermodynamic parameters of aminoglycoside-target interactions under different conditions before making attributions to specific sites and their effects on these global parameters.

Calorimetry↗

PubMed2003

Loss of enzyme-sensitive antigens due to the presence of leukocytes, neomycin sulfate, and LISS.

Previous studies have shown that RBCs with residual WBCs stored in LISS and neomycin sulfate develop characteristics associated with enzyme-treated RBCs. During a mass screening program to antigen type donor RBCs, we observed that the Fya antigens on a RBC sample from an in-house panel became non-detectable with anti-Fya after incubation overnight in Diluent 2 from Micro Typing Systems, Inc. (MTS, Pompano Beach, FL). In response to this observation, we initiated an investigation to determine the cause. Tests were performed according to the manfacturer's instructions in MTS neutral gel cards or gel cards containing anti-IgG. We found that a reduction or loss of the Fya, Fyb, and M antigens occurs when RBCs were prepared from samples containing residual WBCs (as a source of enzymes) and subsequently incubated in media containing neomycin sulfate and LISS. We showed that the effect did not occur in the absence of neomycin sulfate. RBC antigens can be altered in LISS if they have first been exposed to neomycin. We recommend restricting the use of RBCs suspended in MTS Diluent 2 to the day of dilution (as indicated in the package insert) if preparing reagent RBCs from sources that were not leukoreduced and were stored in the presence of neomycin.

Journal Article↗

PubMed1965

EFFECTS OF MINERALS ON NEOMYCIN PRODUCTION BY STREPTOMYCES FRADIAE.

A study was made on the mineral requirements of Streptomyces fradiae strain 3535 for neomycin production. It was observed that optimal levels of the elements Ca, Fe, and Zn per milliliter of a synthetic medium for neomycin production were 10.8, 1.0, and 0.115 mug, respectively. K(2)HPO(4) was required at a concentration of 0.1% for maximal yield of neomycin, whereas NaCl and the metals Mn and Cu were without any effect. High doses of Zn (0.23 mug/ml or above) caused destruction of neomycin after the fifth day of fermentation.

Calcium↗

PubMedDate not supplied

Oral neomycin sulfate and erythromycin base before colon surgery: a comparison of serum and tissue concentrations.

It is accepted that the use of oral neomycin sulfate and erythromycin base before colon surgery results in decreased numbers of intestinal bacteria. Intraluminal levels of these agents are reported to be very high, but systemic availability is still debated. The systemic levels were studied in 8 patients undergoing colon surgery. Each patient received neomycin sulfate and erythromycin base, 1 g each, 19, 18 and 9 hours preoperatively. Twelve samples from serum, one from wound muscle and one from the intestinal wall were obtained from each patient in the 26 hours after the initial dose. Considerable variation was observed among levels. The following means were calculated: peak serum levels were 3.4 and 0.59 micrograms/ml, muscle levels were 1.68 and 0.23 micrograms/g and intestinal wall levels were 6.4 and 12.9 micrograms/g for erythromycin and neomycin respectively. Observed times to peak levels were 19 and 12 hours after the initial dose for erythromycin and neomycin respectively. The detectable systemic concentrations that result when these agents are given orally for bowel preparation before colon surgery may contribute to the drugs' efficacy.

Adult↗

PubMed1984

High-performance liquid chromatographic analysis of neomycin in petrolatum-based ointments and in veterinary formulations.

A high-performance liquid chromatographic (HPLC) method has been developed for the assay of neomycin in petrolatum-based ophthalmic and topical ointments and in veterinary formulations. Neomycin assay interferences from drugs, such as bacitracin and polymyxin B and inactive components, e.g. wax, were eliminated by a methanol wash and/or a partitioning method. The extracted neomycin was derivatized with 2,4-dinitrofluorobenzene followed by normal-phase HPLC with detection at 254 nm. The average recovery of neomycin from spiked samples was approximately 100% with a relative standard deviation of less than 1%.

Bacitracin↗

PubMed1993

Neomycin and spermine have similar effects on secretion and phosphoinositide metabolism in ATP-depleted permeabilized adrenal chromaffin cells.

To evaluate the requirement of bovine adrenal chromaffin cells for inositol phospholipids in secretion, the effects of neomycin and spermine on secretion and phosphoinositide metabolism were compared. Spermine and neomycin had virtually identical effects on secretion and phosphoinositide levels. Both polyamines 1) partially maintained secretion when added to permeabilized cells in the absence of ATP, 2) had no effect when added to cells in the presence of ATP and 3) inhibited secretion when present with the Ca2+ stimulus. In the absence of ATP the enhancements to secretion due to incubation with either polyamine were associated with sustained levels of the polyphosphoinositides. The ability of spermine and neomycin to maintain secretion and the polyphosphoinositides in the absence of ATP supports the hypothesis that the maintenance of the polyphosphoinositides is necessary for secretion. Neomycin was found to inhibit Ca2+ stimulated production of both inositol bis- and tris-phosphates while spermine was found to selectively inhibit inositol bis-phosphate production and had no effect on Ca(2+)-stimulated inositol tris-phosphate production in permeabilized cells.

Adenosine Triphosphate↗

PubMed2001

Neomycin inhibits the angiogenic activity of fibroblast and epidermal growth factors.

Neomycin has been shown to block nuclear translocation of angiogenin in endothelial cells, thereby inhibiting its capacity to induce angiogenesis. We report here that neomycin is also an effective inhibitor of angiogenesis induced by acidic fibroblast growth factor, basic fibroblast growth factor, and epidermal growth factor, all of which undergo nuclear translocation, but not that of vascular endothelial growth factor which does not undergo nuclear translocation. Blocking nuclear translocation, therefore, seems to be a general mechanism for the antiangiogenesis action of neomycin applicable to those angiogenic factors that require nuclear translocation for angiogenesis. These results along with the known toxicity and pharmacokinetics profiles make neomycin and its analogues good candidate inhibitors of angiogenesis that might be developed as antitumor agents.

Active Transport, Cell Nucleus↗

PubMed1998

Binding of neomycin-class aminoglycoside antibiotics to the A-site of 16 S rRNA.

Aminoglycoside antibiotics that bind to ribosomal RNA in the aminoacyl-tRNA site (A-site) cause misreading of the genetic code and inhibit translocation. We have recently solved the structure of an A-site RNA-paromomycin complex. The structure suggested that rings I and II, common to all aminoglycosides that bind to the A-site, are the minimum motif for specific ribosome binding to affect translation. This hypothesis was tested biochemically and with a detailed comparative NMR study of interaction of the aminoglycosides paromomycin, neomycin, ribostamycin, and neamine with the A-site RNA. Our NMR data show that rings I and II of neomycin-class aminoglycosides are sufficient to confer specificity to the binding of the antibiotics to the model A-site RNA. Neomycin, paromomycin, ribostamycin and neamine bind in the major groove of the A-site RNA in a unique binding pocket formed by non-canonical base pairs and a bulged nucleotide. Similar NMR properties of the RNA and the diverse antibiotics within the different complexes formed with neomycin, paromomycin, ribostamycin and neamine suggest similar structures for these complexes.

Anti-Bacterial Agents↗

PubMed2001

Effects of daily oral administration of rifaximin and neomycin on faecal aerobic flora in rats.

The aim of this study was to compare the influence of rifaximin and neomycin on faecal flora in rats. The study was performed on 18 Wistar rats (three groups of six male animals). Group 1 received rifaximin (50 mg kg(-1)/day), group 2, neomycin (50 mg kg(-1)/day) and group 3 was used as control. Drugs were administered orally, once daily for 3 days. Faecal specimens, collected from each rat on day 3, were cultured for the quantitative and qualitative determination of aerobic microorganisms. Rifaximin treatment produced a marked reduction in the number of total aerobic bacteria and Salmonellae; neomycin caused reduction in Salmonellae, but did not cause statistically significant changes in total aerobic bacterial count. The binding of neomycin with faeces could explain this limited activity, which does not correlate with the in vitro susceptibility of the organism affected. These results confirm that rifaximin is suitable for topical treatment to reduce selected bacterial load in the gut intestines.

Administration, Oral↗

PubMed1978

Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy. A controlled, double-blind clinical trial.

In a double-blind, randomized study the efficacy of lactulose was compared with neomycin-sorbitol in 45 episodes of acute nitrogenous portal-systemic encephalopathy (PSE) induced by dietary protein, azotemia, or gastrointestinal hemorrhage. All patients had underlying cirrhosis, and at the time of randomization had encephalopathy of at least grade 2 severity and arterial ammonia concentrations greater than 150 microgram/100 ml. Two thirds of the patients in each group returned to normal mental status and more than 80% in each group showed at least one grade improvement in mental state. In addition, there was equivalent improvement in asterixis, in the performance of the Number Connection Test, in the electroencephalographic pattern, and in arterial ammonia concentration. The principal difference between the two groups was a greater reduction in stool pH after lactulose therapy than after neomycin-sorbitol therapy. One patient randomized to neomycin-sorbitol had to be withdrawn from the study because of persistent vomiting related to the administration of the medication. Otherwise there were no complications attributable to therapy in either group. These data suggest that neomycin-sorbitol and lactulose are equally effective in the treatment of acute nitrogenous portal-systemic encephalopathy.

Clinical Trials as Topic↗

PubMed1996

Failure of neuromuscular blockade reversal after rocuronium in a patient who received oral neomycin.

PURPOSE: Because the aminoglycoside antibiotics and nondepolarizing muscle relaxants have interactions that vary, it is necessary to update the potential for such interactions when new drugs are introduced clinically. Rocuronium is a newly released steroidal nondepolarizing muscle relaxant with an intermediate duration of action. The following report is the first description of prolonged neuromuscular blockage after rocuronium in a patient who had received oral neomycin in anticipation of open bowel resection. CLINICAL FEATURES: A 71-yr-old woman with a two week history of bleeding pr was scheduled for exploratory laparotomy and right hemicolectomy. She received two standard bowel preparations consisting of oral erythromycin and neomycin over a two day period. Rocuronium was used to facilitate tracheal intubation and maintain muscle relaxation during a two hour operation. Despite clinical appearance of reversal of neuromuscular blockade after neostigmine and glycopyrolate, the patient complained of dyspnoea and weakness upon tracheal extubation and required reintubation twice. The reason for prolonged muscle relaxation was thought to be secondary to a rocuronium and neomycin interaction. CONCLUSION: Rocuronium, a new nondepolarizing muscle relaxant, has potential interactions with other drugs including the aminoglycoside antibiotics. This clinical report describes the failure of neuromuscular blockade reversal in a patient who received oral neomycin in anticipation of open bowel resection.

Administration, Oral↗

PubMed1986

Oral neomycin and erythromycin compared with single-dose systemic metronidazole and ceftriaxone prophylaxis in elective colorectal surgery.

A prospective randomized trial was performed to compare oral neomycin and erythromycin with single-dose intravenous metronidazole and ceftriaxone in elective colorectal surgery. The study was discontinued after 60 patients were entered. The overall rate of infection was 41 percent in the oral neomycin and erythromycin group (n = 29) compared with 9.6 percent in those who received intravenous metronidazole and ceftriaxone (n = 31) (p less than 0.01). Infections in the oral group were principally due to resistant Staphylococcus aureus, Bacteroides fragilis, and Escherichia coli. Preoperative administration of oral neomycin and erythromycin was associated with a significant reduction of Escherichia coli counts (1 X 10(7) to 3 X 10(5) organisms/ml, p less than 0.05) compared with the intravenous group, but there was no significant reduction in the counts of Bacteroides fragilis (2 X 10(8) to 1 X 10(7) organisms/ml) and there was an increase in the counts of Clostridia (2 X 10(4) to 1 X 10(6) organisms/ml). These results indicate that single-dose systemic prophylaxis with appropriate antibiotics is superior to oral neomycin and erythromycin.

Administration, Oral↗

PubMed1987

Neomycin is a potent agent for arachidonic acid release in human platelets.

Neomycin (10 microM - 1 mM) was found to induce considerable release of [3H]arachidonic acid from phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine in saponin-permeabilized human platelets prelabeled with [3H]arachidonic acid. The magnitude of arachidonate liberation was almost equal to that induced by A23187 (400 nM) or even greater than that caused by thrombin (1 U/ml). Moreover, neomycin enhanced arachidonic acid release induced by thrombin. Since no significant formation of diacylglycerol and phosphatidic acid via phospholipase C was observed, the arachidonate liberation was considered to be mainly catalyzed by phospholipase A2 action. Addition of neomycin (100 microM) to 45Ca2+-preloaded platelets elicited 45Ca2+ mobilization from intracellular stores. These results indicate evidence that neomycin evokes Ca2+ mobilization from internal stores, which leads to activation of phospholipase A2 to release arachidonic acid in human platelets.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1988

Evidence that neomycin inhibits plasma membrane Ca2+ inflow in isolated hepatocytes.

The effects of neomycin on Ca2+ fluxes and inositol polyphosphates in hepatocytes were investigated since it has been proposed that this antibiotic inhibits inositol 1,4,5-triphosphate formation in fibroblasts [D. H. Carney, D. L. Scott, E. A. Gordon and E. F. LaBelle, Cell 42, 479 (1985)]. In hepatocytes incubated at 1.3 mM extracellular Ca2+ (Ca2+o) neomycin (2 mM) inhibited 45Ca2+ exchange both in the presence or absence of vasopressin. At 1.3 mM Ca2+o, but not at higher concentrations of Ca2+o, the antibiotic (2 mM) inhibited the increase in glycogen phosphorylase a activity observed at late but not at early times after addition of vasopressin. The antibiotic also inhibited the increase in phosphorylase activity caused by the subsequent addition of 1.3 mM Ca2+o to cells previously incubated in the presence of vasopressin and in the absence of added Ca2+o. The concentration of the antibiotic (2 mM) which gave half-maximal inhibition of phosphorylase activation by vasopressin had no effect on the activation of phosphorylase by glucagon or the release of Ca2+ from intracellular stores induced by vasopressin. At a concentration of 10 mM, neomycin caused a 50% inhibition of the formation of [3H]inositol polyphosphates induced by vasopressin. It is concluded that neomycin, at concentrations which inhibit phosphoinositide-specific phospholipase C in other types of cells inhibits the inflow of Ca2+ across the plasma membrane but does not inhibit inositol trisphosphate formation in hepatocytes.

Animals↗

PubMed1992

Sperm-induced currents at fertilization in sea urchin eggs injected with EGTA and neomycin.

Membrane currents were measured in single voltage-clamped sea urchin eggs (Lytechinus pictus and Lytechinus variegatus) that were injected with either EGTA or neomycin and inseminated. Although egg activation and the fertilization calcium wave were prevented by injection of either of these compounds, sperm attached and still elicited inward currents. Sperm-induced currents in EGTA-injected eggs had an abrupt onset, quickly reached a maximum, and then slowly declined in amplitude. Sperm incorporation occurred readily in EGTA-injected eggs. Similar results were obtained with another calcium chelator, BAPTA. In neomycin-injected eggs, sperm-induced currents generally had an abrupt onset and, in contrast to EGTA-injected eggs, the currents usually cut off rapidly. Sperm failed to enter the neomycin-injected eggs and the duration of sperm-induced currents in neomycin-injected eggs was markedly dependent upon the voltage-clamp holding potential, with shorter duration currents occurring at -70 than at -20 mV. The lability of the initial interaction between sperm and egg at negative holding potentials may explain why activation often fails when the egg membrane is voltage clamped at these potentials (Lynn et al., Dev. Biol. 128, 305-323, 1988).

Animals↗

PubMed1988

Stimulation and inhibition of human platelet membrane high-affinity GTPase by neomycin.

The effect of the inositol phospholipid-binding antibiotic neomycin was studied on high-affinity GTPase in human platelet membranes. At low concentrations (up to 1 mM), neomycin by itself stimulated a high-affinity GTPase. This GTPase stimulation was additive with that caused by the hormonal factors, prostaglandin E1 and epinephrine, but not with thrombin. At concentrations higher than 1 mM, neomycin reduced control GTPase activity and eliminated the stimulation caused by thrombin. The data suggest that neomycin by a presently unknown mechanism can regulate activity states of signal transducing GTP-binding proteins.

Blood Platelets↗

PubMed1986

The effects of mevinolin and neomycin alone and in combination on plasma lipid and lipoprotein concentrations in type II hyperlipoproteinemia.

The reduction of elevated low density lipoprotein (LDL) cholesterol concentrations in patients with Type II hyperlipoproteinemia leads to improved cardiovascular morbidity and mortality. Two agents which may be of value in treating hypercholesterolemia are mevinolin and neomycin. Since these drugs lower cholesterol levels through complementary mechanisms, we evaluated the effects of mevinolin and combined mevinolin-neomycin treatment on plasma lipoprotein concentrations in 21 type II hyperlipoproteinemic patients. Mevinolin reduced total and LDL cholesterol concentrations by 24% and 31% respectively (P less than 0.001) and 81% of the patients reduced their LDL cholesterol levels to less than 200 mg/dl. Although the addition of neomycin to mevinolin treatment further lowered total (5%) and LDL (4%) cholesterol concentrations, it also reduced HDL cholesterol levels (19%) (P less than 0.05). Therefore mevinolin normalizes the plasma lipid concentrations in patients with type II hyperlipoproteinemia and combined mevinolin and neomycin treatment offers no advantage over mevinolin-only therapy. In addition, these findings emphasize the importance of determining the HDL cholesterol level to fully evaluate the effects of hypolipidemic therapy.

Cholesterol, HDL↗