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The Journal of Antibiotics May 1984Cellular uptake of habekacin, 1-N-(4-amino-2-hydroxybutyryl)dibekacin, was studied by incubating exponentially growing culture of Escherichia coli Q13 and its...
Cellular uptake of habekacin, 1-N-(4-amino-2-hydroxybutyryl)dibekacin, was studied by incubating exponentially growing culture of Escherichia coli Q13 and its kanamycin-resistant mutants with [3H]habekacin. Kanamycin-resistant mutants, in which the resistance is due to alteration of ribosomes, were cross-resistant to habekacin, and showed a lower uptake of [3H]habekacin than the parental cells, suggesting that binding to ribosomes accelerates cellular uptake of habekacin. Cellular accumulation of [3H]habekacin by wild type cells was markedly inhibited by low temperature and by 2,4-dinitrophenol, suggesting that uptake of habekacin involves energy-dependent transport. The uptake of [3H]habekacin was reduced by various aminoglycoside antibiotics, suggesting common transport systems and/or common internal binding sites on the ribosome. Intracellular accumulation of [3H]dibekacin was reduced by habekacin, suggesting that both antibiotics possess a common transport system and/or common binding sites on the ribosome. Dibekacin was a better competitor than amikacin, suggesting that the dibekacin moiety of habekacin molecule, but not the 4-amino-2-hydroxybutyryl moiety, participates in the transport and/or binding to the ribosome. Binding of [3H]habekacin to E. coli ribosomes was reversed by various aminoglycosides and the degree of inhibition paralleled the one of cellular uptake, suggesting that competition by aminoglycosides for the habekacin uptake occurs at the ribosomal level.
Topics: 2,4-Dinitrophenol; Aminoglycosides; Anti-Bacterial Agents; Bacteria; Dibekacin; Dinitrophenols; Escherichia coli; Ribosomes; Tritium
PubMed: 6376453
DOI: 10.7164/antibiotics.37.596 -
The Journal of Antibiotics Apr 1984
Comparative Study
Topics: Amikacin; Anti-Bacterial Agents; Bacteria; Dibekacin; Kanamycin; Microbial Sensitivity Tests; Species Specificity; Structure-Activity Relationship
PubMed: 6547135
DOI: 10.7164/antibiotics.37.428 -
The Journal of Antibiotics Mar 1984A study was made of the serum levels and of the pharmacokinetic parameters of dibekacin after administration by intravenous infusion at a dose of 2 mg/kg of the drug to...
A study was made of the serum levels and of the pharmacokinetic parameters of dibekacin after administration by intravenous infusion at a dose of 2 mg/kg of the drug to rabbits using different infusion times. The peak serum level (Cmax) was seen to decrease progressively on increasing infusion time. The maximum value of Cmax was obtained after administration of the antibiotic by single bolus injection with an average value of 18.297 +/- 9.694 micrograms/ml, while the minimum value was obtained after intravenous infusion over 1 hour, with an average value of 6.597 +/- 1.250 micrograms/ml. A series of linear relationships was established between different pharmacokinetic parameters and the infusion time and a decrease was observed in the pharmacokinetic parameters alpha, K12, K21 and K13 when the infusion time was increased. Changes were also observed in the distribution kinetics of dibekacin in the rabbit on varying the infusion conditions, suggesting alterations in the access and permanence of the antibiotic in tissues.
Topics: Animals; Dibekacin; Infusions, Parenteral; Kanamycin; Kinetics; Male; Models, Biological; Rabbits; Time Factors
PubMed: 6725142
DOI: 10.7164/antibiotics.37.285 -
Biochemical Pharmacology Feb 1984Previous studies [Laurent et al., Biochem. Pharmac. 31, 3861 (1982)] have demonstrated that aminoglycoside antibiotics bind to negatively charged phospholipid bilayers...
Previous studies [Laurent et al., Biochem. Pharmac. 31, 3861 (1982)] have demonstrated that aminoglycoside antibiotics bind to negatively charged phospholipid bilayers and inhibit the activity of lysosomal phospholipases. This inhibition also occurs in vivo in animal and man. It is considered to be an early and significant step in the development of aminoglycoside-induced nephrotoxicity. The binding of 6 aminoglycosides in current clinical use (dibekacin, gentamicin, tobramycin, kanamycin A, amikacin and streptomycin) to phosphatidylinositol has been studied by gel filtration technique and by conformational analysis. Variation of the phosphatidylinositol content from 0 to 27% of total phospholipids causes a cooperative increase in aminoglycoside binding. At fixed phosphatidylinositol concentration, the binding of the different aminoglycosides is related to the number of aminogroups carried by the drug (viz., gentamicin greater than kanamycin A greater than streptomycin) and is largely, but not entirely dependent upon electrostatic interactions. Conformational analysis of the interaction of aminoglycosides with phosphatidylinositol monolayers was made by a step-wise computation approach. We first have taken into account the Vander Waals, torsional and electrostatic energies and we have calculated the hydrophobic and hydrophilic centers of each molecule. Assembly was then computed by successive association of one molecule of drug and up to 4 molecules of phosphatidylinositol. The calculated interaction energies varied from -8.5 kcal/mol (gentamicin) to -4.9 kcal/mol (amikacin) and -3.9 kcal/mol (streptomycin).(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Aminoglycosides; Anti-Bacterial Agents; Liposomes; Molecular Conformation; Phosphatidylinositols; Phospholipids
PubMed: 6704179
DOI: 10.1016/0006-2952(84)90319-8 -
Antimicrobial Agents and Chemotherapy Feb 1984The role of the tubular reabsorption of aminoglycosides in nephrotoxicity was considered. The tubular reabsorption rate, fractional reabsorption, and net balance,...
The role of the tubular reabsorption of aminoglycosides in nephrotoxicity was considered. The tubular reabsorption rate, fractional reabsorption, and net balance, expressed as the excreted to infused aminoglycoside ratio, were concomitantly studied in male rabbits by continuous infusion of gentamicin, netilmicin, dibekacin, and amikacin. Aminoglycoside nephrotoxicity was evaluated by creatinine levels in serum and pathological renal damage after 14 days of a low- or high-dose regimen, comprising either eight, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (4 mg/kg) or amikacin (16 mg/kg); twelve, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (15 mg/kg) or amikacin (60 mg/kg); or injections of saline for the control group. Aminoglycosides exhibited three degrees of tubular reabsorption: gentamicin had the highest, netilmicin had the lowest, and dibekacin and amikacin had intermediate degrees of reabsorption. Nephrotoxicity associated with alteration in renal histology was observed with gentamicin and, to a lesser extent, with dibekacin in the high-dose regiment. No nephrotoxicity was noted with netilmicin or amikacin compared with the control group. Concentrations of the aminoglycosides in renal cortex and serum were not predictive of renal toxicity. Except for amikacin, which appeared to exhibit the lowest intrinsic renal toxicity, nephrotoxicity was correlated with the tubular reabsorption of each aminoglycoside. It was concluded that aminoglycoside renal toxicity can be determined by two major factors: importance of transport into tubular cells and intrinsic intracellular toxicity.
Topics: Amikacin; Aminoglycosides; Animals; Anti-Bacterial Agents; Blood Proteins; Dibekacin; Gentamicins; Kidney Diseases; Kidney Tubules; Male; Netilmicin; Protein Binding; Rabbits
PubMed: 6712201
DOI: 10.1128/AAC.25.2.168 -
Antimicrobial Agents and Chemotherapy Feb 1984The relationship between plasmid-coded aminoglycoside 2"-O-nucleotidyltransferase [ANT(2")] activity and the minimum inhibitory concentration for aminoglycosides was...
The relationship between plasmid-coded aminoglycoside 2"-O-nucleotidyltransferase [ANT(2")] activity and the minimum inhibitory concentration for aminoglycosides was studied. ANT(2") was very unstable, and therefore, procedures for handling this enzyme were optimized. Escherichia coli L58058.1 producing ANT(2") was resistant to gentamicin, sisomicin, kanamycin, tobramycin, and dibekacin but susceptible to netilmicin, amikacin, and neomycin. However, only amikacin and neomycin were not modified by ANT(2"). A correlation between the substrate profile of the enzyme tested at 0.15 mM and the minimum inhibitory concentrations of the aminoglycosides could not be demonstrated. The substrate concentration-dependent enzyme activity curves proved to be a better alternative than a substrate profile based on tests at one concentration. At concentrations of greater than 10(-2) mM, ANT(2") demonstrated substrate inhibition that explains the discrepancy between ANT(2") activity and the minimum inhibitory concentrations. A close correlation was found between the physiological efficiency (Vmax/Km ratio) of ANT(2") and the minimum inhibitory concentrations for the enzyme-producing strain.
Topics: Aminoglycosides; Anti-Bacterial Agents; Chromatography, Affinity; Conjugation, Genetic; Drug Resistance, Microbial; Escherichia coli; Kinetics; Nucleotidyltransferases
PubMed: 6324668
DOI: 10.1128/AAC.25.2.234 -
Hinyokika Kiyo. Acta Urologica Japonica Jan 1984Dibekacin (DKB) was administered to patients with complicated urinary tract infections without any indwelling catheter to evaluate objectively and comparatively the... (Clinical Trial)
Clinical Trial Comparative Study
Dibekacin (DKB) was administered to patients with complicated urinary tract infections without any indwelling catheter to evaluate objectively and comparatively the efficacy, safety and usefulness of intravenous drip infusion once daily and twice daily in a well-controlled study. A 50 mg dose of DKB was administered twice a day to group A, and a 100 mg dose was given once a day to group B. In both groups the drug was given by 1-hr i.v. infusion for 5 consecutive days. Drug efficacy was evaluated in 72 (group A: 36, group B: 36) of the 83 patients treated, and the safety was evaluated on 81 patients (group A: 41, group B: 40). There were no significant differences in the background characteristics between the two groups. The overall clinical efficacy judged by the Committee for Evaluation of Clinical Efficacy was "excellent" in 14% and "moderate" in 50% of group A, and "excellent" in 17% and "moderate" in 64% of group B, the efficacy being higher for group B than group A, but the difference was not statistically significant. The overall drug efficacy rate for each type of infection excluding group 2, was slightly higher in group B, but this difference was not significant either. The overall clinical efficacy for each site of infection, was higher for group B but the differences were not significant. The overall clinical efficacy as judged by the attending physicians was "excellent" in 17% and "moderate" in 58% of group A, and "excellent" in 25% and "moderate" in 61% of group B. The intergroup difference was thus smaller than that judged by the Committee. The elimination rates against bacteriuria were 58% for both groups A and B, and the decrease rates including "cleared" were 42% against pyuria for both groups A and B. Bacteriological evaluation, showed that there was no significant difference in the eradication rates, between group A (65%) and group B (70%). But the eradication rate for gram-positive bacteria was 40% in group A and 81% in group B, there being a significant difference (P less than 0.05) between them. The evaluation of usefulness gave 44% and 53% "satisfactory" rates, respectively, for groups A and B. The results for the "average score" were also the same in both groups. There were no side effects in any of the 81 patients examined. Abnormal laboratory test values attributed to the drug were seen only in 3 and 2 patients in groups A and B, respectively, there being no difference between the groups.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacteria; Clinical Trials as Topic; Dibekacin; Drug Administration Schedule; Drug Resistance, Microbial; Female; Humans; Infusions, Parenteral; Kanamycin; Male; Middle Aged; Urinary Tract Infections
PubMed: 6375317
DOI: No ID Found -
The Journal of Antibiotics Dec 1983Actinomycetes were characterized in terms of resistance to 11 different aminoglycoside antibiotics (AGs). Strains freshly isolated in AG containing media showed wide... (Comparative Study)
Comparative Study
Actinomycetes were characterized in terms of resistance to 11 different aminoglycoside antibiotics (AGs). Strains freshly isolated in AG containing media showed wide varieties of multiple AG resistance, while the majority of ISP (International Streptomyces Project) cultures and the actinomycete strains isolated in an AG free medium were susceptible to all or most of the AGs tested. Marked characteristics were noted in multiple AG resistance of gray and yellow colored actinomycetes and AG-producing strains. In gray colored isolates, multiple resistance to kanamycin A, dibekacin, ribostamycin, butirosin A, istamycin A and neamine was often observed. Yellow colored isolates having multiple AG resistance were mostly resistant to neamine, ribostamycin and streptomycin and, to a lesser extent, istamycin A, dibekacin and butirosin A. Most of the AG producers tested showed unique multiple AG resistance patterns.
Topics: Actinomycetales; Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Microbial; Species Specificity; Streptomyces; Structure-Activity Relationship
PubMed: 6662815
DOI: 10.7164/antibiotics.36.1748 -
Antimicrobial Agents and Chemotherapy Nov 1983The molecular basis for activity of habekacin was studied by using Escherichia coli Q-13. Electron microscopic studies revealed that numerous blebs, derived from the...
The molecular basis for activity of habekacin was studied by using Escherichia coli Q-13. Electron microscopic studies revealed that numerous blebs, derived from the outer membrane, were formed on cells treated with habekacin. Cytoplasmic contents leaked into the lumina of blebs, and the membrane of some enlarged blebs was disrupted. In a cell-free system, habekacin interfered with polypeptide synthesis, caused codon misreading, and inhibited translocation of N-acetylphenylalanyl-tRNA from the acceptor site to the donor site on ribosomes. [3H]habekacin bound to both 50S and 30S ribosomal subunits. The current experiments indicated that the mechanism of action of habekacin is similar to that of 2-deoxystreptamine-containing aminoglycoside antibiotics such as dibekacin, kanamycin, gentamicin, and related substances. The relationship of membrane damage to inhibition of ribosomal functions remains to be determined.
Topics: Aminoglycosides; Anti-Bacterial Agents; Codon; Dibekacin; Escherichia coli; Peptide Biosynthesis; RNA, Transfer, Amino Acyl; Ribosomes; Translocation, Genetic
PubMed: 6362557
DOI: 10.1128/AAC.24.5.797 -
Journal of Biochemistry Oct 1983An antiserum against kanamycin (anti-KM) was elicited in rabbits immunized with a kanamycin immunogen prepared by a three-step procedure using... (Comparative Study)
Comparative Study
Enzyme immunoassays of kanamycin group antibiotics with high sensitivities using anti-kanamycin as a common antiserum: reasoning and selection of a heterologous enzyme label.
An antiserum against kanamycin (anti-KM) was elicited in rabbits immunized with a kanamycin immunogen prepared by a three-step procedure using N-(m-maleimidobenzoyloxy)succinimide as a cross-linker. KM and tobramycin (TOB) were labeled with beta-D-galactosidase utilizing another cross-linker, N-(gamma-maleimidobutyryloxy)succinimide. The labeled KM showed very strong affinity to anti-KM antiserum and that of TOB had an adequate affinity to anti-KM. Increases in the assay sensitivities at the B/B0 value of 50% of KM and dibekacin were 183- and 191,000-times, respectively, on changing the enzyme label from KM to TOB. The optimal conditions for highly sensitive enzyme immunoassay (EIA) of KM using anti-KM and the enzyme labeled with TOB with satisfactory accuracy and precision were determined. Highly sensitive EIAs of four KM analogs with measurement ranges of 1 to 100 ng/tube were also developed using the labeled TOB and anti-KM as common reagents. Various commonly used drugs were found to have little reactivity in this immunoassay, indicating that the EIA is specific to KM and its analogs. The reasoning and the selection of TOB as the label are also discussed.
Topics: Adjuvants, Immunologic; Animals; Cross Reactions; Immune Sera; Immunoenzyme Techniques; Kanamycin; Rabbits; Structure-Activity Relationship
PubMed: 6361009
DOI: 10.1093/oxfordjournals.jbchem.a134461