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PubMed2024

Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract.

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota. Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.

Animals↗
PubMed1998

Neomycin inhibits angiogenin-induced angiogenesis.

A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor. Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis. The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect. In contrast, genistein, oxophenylarsine, and staurosporine, inhibitors of tyrosine kinase, phosphotyrosine phosphatase, and protein kinase C, respectively, do not inhibit nuclear translocation of angiogenin. Neomycin inhibits angiogenin-induced proliferation of human endothelial cells in a dose-dependent manner. At 50 microM, neomycin abolishes angiogenin-induced proliferation but does not affect the basal level of proliferation and cell viability. Other aminoglycoside antibiotics, including gentamicin, streptomycin, kanamycin, amikacin, and paromomycin, have no effect on angiogenin-induced cell proliferation. Most importantly, neomycin completely inhibits angiogenin-induced angiogenesis in the chicken chorioallantoic membrane at a dose as low as 20 ng per egg. These results suggest that neomycin and its analogs are a class of agents that may be developed for anti-angiogenin therapy.

Angiogenesis Inducing Agents↗
PubMed1998

Attenuation of neomycin ototoxicity by iron chelation.

Increasing evidence suggests that aminoglycoside ototoxicity is mediated by the formation of an aminoglycoside-iron complex and that the creation of this complex is a preliminary step in generation of free radical species and subsequent hair cell death. In this study we have assessed the ability of the iron chelator deferoxamine to attenuate the hearing loss induced by an ototoxic dose of the aminoglycoside neomycin (100 mg/kg per day for 14 days). Experiments were carried out on pigmented guinea pigs weighing 250 to 300 g. Changes in auditory sensitivity were characterized by monitoring shifts in compound action potential (CAP) thresholds, recorded through indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results show that animals receiving neomycin alone suffered a mean threshold shift exceeding 35 dB at all test frequencies (2.0, 4.0, and 8.0 kHz) 30 days after initiation of treatment. In comparison, all animals receiving cotherapy of neomycin and deferoxamine (150 mg/kg twice daily for 14 days) maintained their CAP threshold, suggesting significant protection from neomycin ototoxicity. A statistical comparison of treatment groups showed that in the animals receiving cotherapy with neomycin and deferoxamine, deferoxamine produced a significant protective effect against neomycin-induced ototoxicity (P < 0.001). These results provide further evidence of the intrinsic role of iron in aminoglycoside ototoxicity and suggest that deferoxamine may have a therapeutic role in attenuating the cytotoxic action of aminoglycoside antibiotics.

Animals↗
PubMed1976

A comparative study of the effects of cholestyramine and neomycin in the treatment of type II hyperlipoproteinaemia.

A comparative study of the effects of cholestyramine and neomycin has been carried out in 35 patients with severe type II hyperlipoproteinaemia. Both agents were administered during a period of 18 weeks, the daily dosages being 12, 16 or 20 g cholestyramine and 1, 1.5 or 2 g neomycin. The mean decrease in cholesterol concentration was 22% with cholestyramine and 23% with neomycin. There was no difference in effect between the two agents and between the doses used. No significant influence on triglyceride concentration and on body weight was observed. No signs of deficiencies in fat-soluble vitamins were found. Anticoagulant requirements increased during cholestyramine medication. No signs of hyperchloraemic acidosis were observed during treatment with colestyramine. Cholestyramine was tolerated less well than neomycin: it had to be discontinued in 8 cases. Neomycin was not tolerated by 3 patients. The majority of the patients preferred neomycin.

Adolescent↗
PubMed1975

Cardiovascular depressant effects of neomycin and gentamicin in rhesus monkeys.

1. The acute cardiovascular effects of neomycin and gentamicin, representative aminoglycoside antibiotics, were examined in surgically-prepared anaesthetized rhesus monkeys. 2. Intravenous administration of 14, 28, and 56 mg/kg of neomycin consistently induced a dose-dependent depression of systemic blood pressure, cardiac output, left ventricular contractile force, maximum dF/dt of left ventricular contraction, and heart rate. Neomycin produced similar cardiovascular depressant effects when heart rate was maintained constant by electrical pacing. 3. Maximum depression of haemodynamic values usually occurred within 2 to 5 min after injection of neomycin; values then gradually returned to control levels within 20 to 30 (14 mg/kg) or 60 to 80 (56 mg/kg) minutes. 4. Injection of CaCl2 (1.35 mEq Ca2+/kg, i.v.) during the peak depressant effect of neomycin produced a rapid and maintained restoration of cardiovascular function to control levels; conversely, noradrenaline (2 mug, i.v.) of isoprenaline (0.5 mug, i.v.) produced only transient reversal of the neomycin effects. 5. Similar evidence of cardiovascular dysfunction was observed with gentamicin. 6. These findings demonstrate the direct cardiovascular depressant effects of aminoglycoside natibiotics in a higher primate species, and suggest that this adverse response is related to an alteration of calcium ion function.

Animals↗
PubMed2004

The influence of amphotericin B and neomycin on the effect of human relaxin-2 on foetal membranes and isolated myometrium.

In vitro studies have documented effects of relaxin on utero-placental tissues. Previously unpublished experiments indicate that neomycin and amphotericin B in vitro influences the effect of human relaxin-2 on the strength of human foetal membranes. The aim of the current study was to investigate the interaction between neomycin and amphotericin B and human relaxin-2 using human foetal membranes, human myometrium and rat myometrium. Chloramphenicol, erythromycin and penicillin were also examined. Human foetal membranes were stretched until rupture in a materials-testing machine while the contractility of rat and human myometrium were examined by myography. Human relaxin-2 (hrlx-2, 10(-9) M) induced a decreased strength in human foetal membranes, although this effect of hrlx-2 was inhibited after co-incubation with neomycin and amphotericin B. Hrlx-2 (10(-9) M) in combination with chloramphenicol induced a decreased strength of human foetal membranes. Hrlx-2 (10(-9) M) decreased myometrial contractility on amplitude and frequency in the rat myometrium, but had no effect on baseline tension. After exposure to amphotericin B, hrlx-2 induced a more pronounced decrease in amplitude, increased baseline tension and increased the frequency of contractions of the rat myometrium. Hrlx-2 (10(-9) M) had no effect on the human myometrium. However, after exposure to amphotericin B or neomycin+amphotericin B, hrlx-2 induced an increase in baseline tension and a decrease in amplitude. Amphotericin B and neomycin+amphotericin B increased the frequency of contractions and this effect was further enhanced by the addition of hrlx-2. We therefore conclude that amphotericin B and neomycin + amphotericin B may have an influence on relaxin's effect on isolated foetal membranes and myometrium.

Amphotericin B↗
PubMed1990

Acute effects of neomycin on slowly adapting type I and type II cutaneous mechanoreceptors in the anaesthetized cat and rat.

1. Slowly adapting type I (SAI) and type II (SAII) mechanoreceptors in the skin were studied in anaesthetized cats and rats employing mechanical stimuli every 30 s. Individual stimuli rose within 200 ms to a plateau force which was kept constant through a feedback control unit for 2000 ms. 2. In cats, close arterial infusion of neomycin (2.5 mg/min) as sulphate was given through a side branch into the femoral blood stream for 5, 10 or 20 min at a rate of 0.025 ml/min. At other times saline was infused at the same rate. 3. After 20 min of neomycin infusion (total 50 mg) nervous discharge of cat SAI receptors was suppressed to about 30% of the control responses before neomycin infusion. Nervous responses were reduced more profoundly during the plateau phase of stimulation than during the dynamic phase. The interspike interval histogram was severely distorted. 4. In contrast, cat SAII receptors maintained about 70% of their control response after 20 min of neomycin infusion. The interspike interval histogram showed an orderly shift towards longer intervals maintaining its normal shape. 5. In rats, intradermal microinfusion of neomycin (30 micrograms/min) through a glass micropipette into the immediate vicinity of the receptor under investigation resulted in severe transient suppression of SAI receptor responses to about 10% of the control level. Receptor responses recovered almost completely about 1 h after the end of neomycin application. 6. It is concluded that the observed differences between the two types of slowly adapting mechanoreceptors are consistent with the hypothesis that the SAI receptor functions as a secondary sensory receptor, with a synaptic link between the Merkel cell and the primary afferent neurone.

Animals↗
PubMed1978

Interaction of neomycin with ribosomes and ribosomal ribonucleic acid.

Neomycin binds ribosomes and ribosomal ribonucleic acid (rRNA) in vivo and in vitro producing changes detectable by increases in gel electrophoretic mobility. These changes were observed in gels that contain ethylenediaminetetraacetic acid or no added magnesium ion. The progressive increase in gel electrophoretic mobility with increasing antibiotic concentrations suggests that neomycin is binding at multiple sites on RNA. The binding was reversible but sufficiently stable to survive dialysis and electrophoresis. It is proposed that bound neomycin stabilizes the ribosome and RNA structures, restricting the unfolding of the particles during electrophoresis and thus allowing for a more rapid migration in the gel. Gentamicin produced an effect similar to that of neomycin. Paromomycin, differing from neomycin by only one amino group, had considerably less effect on ribosome and rRNA mobilities. The binding of neomycin to rRNA improved the linearity of the plot of log molecular weight versus mobility and thus may be of benefit in providing a more accurate estimation of molecular weights of large RNAs.

Anti-Bacterial Agents↗
PubMed1967

Utilization of carbon and nitrogen-containing compounds for neomycin production by Streptomyces fradiae.

A number of carbon and nitrogen compounds were tested for their effect on growth of Streptomyces fradiae 3535 and neomycin production. Dextrin, starch, and maltose were excellent carbon sources for neomycin production, and sodium nitrate, aspartic acid, and glutamic acid were adequate nitrogen sources. Studies on biochemical changes during fermentation in four typical media indicated that there was no direct relation between the growth of the organism and neomycin formation. The pH of the medium might be an important factor for neomycin synthesis. The quantitative formation of neomycin components depended on the variation of carbon and nitrogen sources. On the basis of this study, a suitable synthetic medium for neomycin production has been developed.

Alcohols↗
PubMed1987

Evidence that neomycin inhibits binding of herpes simplex virus type 1 to the cellular receptor.

The effect of neomycin, a phosphoinositide-binding aminoglycoside, on herpes simplex virus type 1 (HSV-1) infection of BHK cells was studied. We showed earlier that it specifically inhibits HSV-1 production but not HSV-2 production (Langeland et al., Biochem Biophys. Res. Commun. 141:198-203, 1986). We now show that neomycin had no effect on cellular protein synthesis, as judged by the appearance of 35S-labeled polypeptides separated by polyacrylamide gel electrophoresis. Virus-induced polypeptides, however, were strongly inhibited at neomycin concentrations above 2 mM. Comparison among different aminoglycosides showed a variation in inhibition of HSV-1 production that paralleled the cationic charge of the aminoglycosides. HSV-1 receptor binding at 4 degrees C was completely inhibited by neomycin. At 37 degrees C both receptor binding and internalization, as measured by an indirect assay, appeared to be inhibited by more than 90%. The effect of neomycin on the infection was almost immediate upon the addition of the drug and preceded virus internalization. Possible mechanisms of the neomycin effect are discussed.

Animals↗
PubMed1989

Neomycin prevents indomethacin-induced gastric peristalsis and mucosal injury in the rat.

Inhibition of prostaglandin synthesis together with vagally mediated peristaltic contractions are essential if mucosal injury is to occur in the stomach of indomethacin-treated rats. The neomycin group of antibiotics has been shown to interfere with acetylcholine release. Agents blocking peristalsis have been demonstrated to prevent mucosal injury. We postulated that neomycin might inhibit peristalsis and prevent lesion formation. The effect of oral neomycin and bacitracin on gastric wall tone and peristaltic response to indomethacin were assessed and related to the lesion score. Bacitracin had no effect on either response and severe injury occurred. Neomycin did not block the tonal response to indomethacin but abolished peristalsis and no injury occurred. Induction of peristalsis with insulin in neomycin-indomethacin treated rats restored mucosal injury. It is concluded that neuromuscular blockade by neomycin prevented mucosal lesions by preventing peristalsis and not by impairing the ability of indomethacin to inhibit prostaglandin synthesis.

Animals↗
PubMedDate not supplied

Turnover of low density lipoproteins during inhibition of cholesterol absorption by neomycin.

The mechanisms for the hypocholesterolemic actin of neomycin were examined in six patients with various levels of plasma total cholesterol and triglycerides. All patients were studied on a metabolic ward. The first period of 6 weeks was for control. Thereafter, neomycin (1.5 g/day) was started, and the patients were readmitted for another 6-week period after 2 to 3 months of treatment with the drug. Cholesterol balance studies showed that neomycin increased fecal excretion of neutral steroids by an average of 45%; the drug also inhibited absorption of exogenous cholesterol by an average of 44%. During treatment with neomycin, the plasma total cholesterol fell by an average of 20%, low density lipoproteins (LDL) fell by 25%, and high density lipoproteins, by 16%. Neomycin did not change plasma triglyceride levels. Turnover of the apoprotein of LDL (apoLDL) was measured following injection of 125I-apoLDL. Neomycin decreased synthesis of apoLDL by 28%. The decrease in plasma apoLDL level was correlated positively with the decrease in apoLDL synthetic rate. The effect of the drug on clearance of LDL was less constant; four of six patients had an increase in fractional clearance rates of apoLDL, but the change for the whole group was not statistically significant. These data suggest that a decrease in production of LDL is a major factor in the lowering of LDL following inhibition of cholesterol absorption; however, an increase in clearance rates may occur in some patients.

Absorption↗
PubMed1980

Importance of adding neomycin to metronidazole for bowel preparation.

A prospective randomized trial has investigated whether it is necessary to add oral neomycin to oral metronidazole as a means of preventing sepsis in elective colonic resection. Seventy-three patients completed the study; 41 received metronidazole and placebo neomycin and 32 received metronidazole and active neomycin. There was a significant reduction in the incidence of wound infection in patients receiving neomycin and metronidazole (22%) compared with metronidazole alone (51%, P<0.02). There was also a significant reduction in anaerobic infections in the group receiving metronidazole and neomycin compared with metronidazole alone (P<0.05). These results indicate that oral metronidazole alone is of no benefit for patients requiring elective colonic operations and that if oral metronidazole is advised it should always be given in combination with oral neomycin.

Administration, Oral↗
PubMed2004

Perivascular delivery of neomycin inhibits the activation of NF-kappaB and MAPK pathways, and prevents neointimal hyperplasia and stenosis after arterial injury.

The nuclear transcription factor kappaB (NF-kappaB) is a cytoplasmic dimer that, as the family of mitogen-activated protein kinase (MAPK), can directly regulate the expression of early genes and genes involved in the stress response, following a variety of physiological or pathological stimuli. Both of them stimulate the transcription of many proteins, which are considered important during inflammation. A crucial role has been assigned to these factors in cellular proliferation and in neointimal hyperplasia secondary to the endothelial lesion of arterial vessels. On the other hand, it has been described that neomycin can have an inhibitory function on tumor cell proliferation, through the inhibition of different intracellular pathways of signaling, among them the NF-kappaB and MAPK pathways. Rat common carotid artery was subjected to balloon angioplasty. Neomycin sulfate (18 mg) was applied using pluronic acid gel on the adventitial surface of the injured vessel. MAPK and NF-kappaB activation was quantified after 24 hours with immunohistochemical staining. Neointimal formation was quantified after 14 days with morphometry. Immunohistochemistry results demonstrating MAPK and NF-kappaB activation reveal that both transcription factors are activated in the media of the control vessel wall. In contrast, the immunoreactivity for MAPK and NF-kappaB in the sections obtained from arteries treated with neomycin over 24 hours was insufficient or nonexistent. Treatment with neomycin on adventitia over 14 days in arteries on which angioplasty was performed shows a neointimal index (intimal area/medial area) decrease of 71% in comparison with arteries that were not treated. The adventitial neomycin treatment over 14 days produces a very significant increase (287.5%; p<0.0001) in the arterial luminal circumference in comparison with arteries treated with vehicle. These results support the theory that neomycin plays an important role against neointimal hyperplasia through the inhibition of MAPK and NF-kappaB activation.

Animals↗
PubMed2003

Investigations on neomycin production with immobilized cells of Streptomyces marinensis NUV-5 in calcium alginate matrix.

The purpose of this investigation was to study the effect of Streptomyces marinensis NUV-5 cells immobilized in calcium alginate for the production of neomycin. The effect of various parameters, such as the effect of alginate concentration (1%, 2%, 3%, 4%, and 5% wt/vol), the effect of cation (CaCl2, BaCl2, and SrCl2), the concentration of cation (0.01M, 0.125M, 0.25M, 0.375M, and 0.5M), the curing times (1, 6, 11, 16, and 21 hours), and the diameter of the bead (1.48, 2.16, 3.24, 4.46, and 5.44 mm), on neomycin production and bead stability were studied. The effect of maltose (4%, 3%, 2%, and 1% wt/vol) and sodium glutamate (0.6%, 0.3%, 0.15%, and 0.075% wt/vol) concentration on neomycin production was also studied. Better neomycin production was achieved with optimized parameters, such as alginate at 2% wt/vol, 0.25M CaCl2, 1-hour curing time, and 3.24 mm bead diameter. Effective neomycin production was achieved with 3% wt/vol maltose and 0.6% wt/vol sodium glutamate concentration. The repeated batch fermentations were conducted (every 96 hours) using the optimized alginate beads, employing the production medium with 3% wt/vol maltose and 0.6% wt/vol sodium glutamate along with mineral salts solution. The increase in antibiotic production was observed up to the 5th cycle, and later gradual decrease in antibiotic production was observed. Comparison of the total antibiotic production with free cells and immobilized cells was also done. An enhanced antibiotic productivity of 32% was achieved with immobilized cells over the conventional free-cell fermentation, while 108% more productivity was achieved over the washed free-cell fermentation. From these results it is concluded that the immobilized cells of S marinensis NUV-5 in calcium alginate are more efficient for the production of neomycin with repeated batch fermentation.

Alginates↗
PubMed2004

Electrostatic mechanisms underlie neomycin block of the cardiac ryanodine receptor channel (RyR2).

Neomycin is a large, positively charged, aminoglycoside antibiotic that has previously been shown to induce a voltage-dependent substate block in the cardiac isoform of the ryanodine receptor (RyR2). It was proposed that block involved an electrostatic interaction between neomycin and putative regions of negative charge in both the cytosolic and luminal mouths of the pore. In this study, we have attempted to screen charge by increasing potassium concentration in single-channel experiments. Neomycin block is apparent at both cytosolic and luminal faces of the channel in all K+ concentrations tested and alterations in K+ concentration have no effect on the amplitudes of the neomycin-induced substates. However, the kinetics of both cytosolic and luminal block are sensitive to changes in K+ concentration. In both cases increasing the K+ concentration leads to an increase in dissociation constant (KD). Underlying these changes are marked increases in rates of dissociation (k(off)), with little change in rates of association (k(on)). The increase in k(off) is more marked at the luminal face of the channel. Changes in K+ concentration also result in alterations in the voltage dependence of block. We have interpreted these data as supporting the proposal that neomycin block of RyR2 involves electrostatic interactions with the polycation forming a poorly fitting "plug" in the mouths of the conduction pathway. These observations emphasize the usefulness of neomycin as a probe for regions of charge in both the cytosolic and luminal mouths of the RyR2 pore.

Ion Channel Gating↗
PubMed1986

Binding of neomycin and calcium to phospholipids and other anionic compounds.

In order to assess the potential importance of different cellular binding sites for the adverse effects of aminoglycosides (i.e. oto- and nephrotoxicity) the binding of neomycin and calcium to phospholipids and other anionic cell constituents was assayed in vitro. Phospholipids demonstrated binding affinities that strongly favored neomycin (Km, 10 to 100 microM) over calcium (Km, 300 to 1,120 microM). Both neomycin and calcium showed strongest binding to lipids with monoester phosphate groups: phosphatidic acid, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-bisphosphate. The lipids bound 0.2 to 0.4 molecules of neomycin and 0.5 to 1 molecule of calcium, respectively, per lipid. Anionic non-lipid compounds such as melanin, gangliosides or chondroitin sulfate were ineffective competitors of neomycin binding to lipids. The results emphasize the importance of phospholipids as cellular binding sites for aminoglycosides. Furthermore, if one considers extra- and intracellular calcium and neomycin concentrations, the relative affinity of lipids for these two compounds suggests an explanation for both the reversible and the essentially irreversible toxic effects of the aminoglycosides.

Aminoglycosides↗
PubMedDate not supplied

Interactions between neomycin and cerebral dopaminergic and serotoninergic transmission in rats.

The aim of this work was to investigate the effects of neomycin on monoamine contents of rat striatal tissue. The analysis was performed by HPLC with electrochemical detection. Rats were injected with neomycin (2 mg/kg; i.p.) and killed at different times over 24 h. The striatal homogenate was injected in a reversed-phase HPLC. Results showed a significant increase in dopamine tissue level (+35 per cent; 4 h after neomycin injection) and a decrease (-36 per cent) in the level of its metabolites. Striatal serotonin level showed a rapid and significant (p < 0.001) increase, +130 per cent, 2 h after neomycin injection. DOPAC/DA and 5HIAA/5HT ratios were reduced by 34 per cent and 46 per cent respectively. These results indicate an inhibitory effect of neomycin on striatal dopaminergic and serotoninergic systems. Several mechanisms could be involved in these effects of neomycin in the biosynthesis process through stimulation of tyrosine hydroxylase and tryptophane hydroxylase and/or MAO and COMT activities. The blockage of calcium channels was also suggested.

Animals↗