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The Journal of Antibiotics Jun 1981The degrees of binding of [3H]dibekacin to LiCl-treated cores of E. coli ribosomes were reduced by increasing LiCl concentrations. The 1.15 M LiCl core lost 70...
The degrees of binding of [3H]dibekacin to LiCl-treated cores of E. coli ribosomes were reduced by increasing LiCl concentrations. The 1.15 M LiCl core lost 70 approximately 80% of the original binding capacity. The antibiotic attachment to the 1.15 M LiCl core was restored by reconstitution with the split proteins (SP), which were obtained by the treatment of 70S ribosomes with LiCl at concentrations of 0.8 approximately 1.15 M. The basic proteins, split off during the transition from 0.4 M LiCl core to 0.8 approximately 1.15 M LiCl core, seemed to be involved in the drug binding. SP0.4 approximately 1.15, which was obtained by the treatment of the 0.4 M LiCl core with 1.15 M LiCl, was fractionated by CM-Sephadex C-25 column chromatography, and each fraction was assayed for protein composition and the capability of restoring the ability of the 1.15 M LiCl core to bind the drug. Of ribosomal proteins eliminated with 1.15 M LiCl, the addition of either S9 or L6 alone to the 1.15 M LiCl core was observed to restore approximately 50% of the binding as compared to the 70S ribosome alone, and both proteins restored about 70% of the binding. The results suggested that ribosomal proteins S9 and L6 were involved in the attachment of [3H]dibekacin to the ribosome. The antibiotic binding to the 70S ribosome and 1.15 M LiCl core reconstituted with S9 and L6 was considerably inhibited by unlabelled dibekacin or kanamycin, and partially inhibited by gentamicin or neomycin, but was not significantly affected by streptomycin or viomycin.
Topics: Aminoglycosides; Anti-Bacterial Agents; Chlorides; Dibekacin; Escherichia coli; Kanamycin; Lithium; Lithium Chloride; Protein Binding; Ribosomal Protein S9; Ribosomal Proteins; Ribosomes
PubMed: 6268595
DOI: 10.7164/antibiotics.34.763 -
Antimicrobial Agents and Chemotherapy Mar 1980The in vitro and in vivo antimicrobial activity of sporaricin A, a new aminoglycoside, was compared with that of amikacin, dibekacin, and gentamicin. Sporaricin A showed... (Comparative Study)
Comparative Study
The in vitro and in vivo antimicrobial activity of sporaricin A, a new aminoglycoside, was compared with that of amikacin, dibekacin, and gentamicin. Sporaricin A showed a broad spectrum of activity against various gram-positive and -negative bacteria, including amikacin-, dibekacin-, or gentamicin-resistant strains. Sporaricin A inhibited more than 90% of clinical isolates of staphylococci, Klebsiella, Enterobacter, Citrobacter, Serratia, and Proteus, except for P. morganii and P. inconstans, at the concentration of 3.13 microgram/ml. This activity, except for that against Serratia, was similar to that of amikacin. Against P. inconstans and S. marcescens, sporaricin A was more effective than amikacin, dibekacin, and gentamicin. However, its activity against Pseudomonas aeruginosa was relatively weak in comparison with three other aminoglycosides. Sporaricin A was highly effective against bacteria that had various aminoglycoside-inactivating enzymes and that were resistant to the other drugs tested, but it was not active against those with aminoglycoside 3-acetyltransferase-I. The activity of sporaricin A tended to be greater with a reduction in inoculum size of bacteria and an increase in medium pH and decreased slightly in the presence of 10 to 50% horse serum. The in vitro activity was confirmed by in vivo tests in experimental infections with various bacteria. Its protective effect seemed to be equal to or greater than that of amikacin or dibekacin.
Topics: Amikacin; Aminoglycosides; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Dibekacin; Gentamicins; Male; Mice
PubMed: 7425599
DOI: 10.1128/AAC.17.3.337 -
Antimicrobial Agents and Chemotherapy Jun 2009We report here the characterization of a novel aminoglycoside resistance gene, aac(6')-Iaf, present in two multidrug-resistant (MDR) Pseudomonas aeruginosa clinical...
We report here the characterization of a novel aminoglycoside resistance gene, aac(6')-Iaf, present in two multidrug-resistant (MDR) Pseudomonas aeruginosa clinical isolates. These isolates, IMCJ798 and IMCJ799, were independently obtained from two patients, one with a urinary tract infection and the other with a decubitus ulcer, in a hospital located in the western part of Japan. Although the antibiotic resistance profiles of IMCJ798 and IMCJ799 were similar to that of MDR P. aeruginosa IMCJ2.S1, which caused outbreaks in the eastern part of Japan, the pulsed-field gel electrophoresis patterns for these isolates were different from that for IMCJ2.S1. Both IMCJ798 and IMCJ799 were found to contain a novel chromosomal class 1 integron, In123, which included aac(6')-Iaf as the first cassette gene. The encoded protein, AAC(6')-Iaf, was found to consist of 183 amino acids, with 91 and 87% identity to AAC(6')-Iq and AAC(6')-Im, respectively. IMCJ798, IMCJ799, and Escherichia coli transformants carrying a plasmid containing the aac(6')-Iaf gene and its upstream region were highly resistant to amikacin, dibekacin, and kanamycin but not to gentamicin. The production of AAC(6')-Iaf in these strains was confirmed by Western blot analysis. Thin-layer chromatography indicated that AAC(6')-Iaf is a functional acetyltransferase that specifically modifies the amino groups at the 6' positions of aminoglycosides. Collectively, these findings indicate that AAC(6')-Iaf contributes to aminoglycoside resistance.
Topics: Acetylation; Acetyltransferases; Aminoglycosides; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Humans; Integrons; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 19349516
DOI: 10.1128/AAC.01360-08 -
Antimicrobial Agents and Chemotherapy Aug 1990Enterococcus faecium BM4102 was resistant to macrolide-lincosamide-streptogramin B-type (MLS) antibiotics; tetracycline-minocycline; and high levels of kanamycin,...
Enterococcus faecium BM4102 was resistant to macrolide-lincosamide-streptogramin B-type (MLS) antibiotics; tetracycline-minocycline; and high levels of kanamycin, neomycin, tobramycin, and dibekacin but not gentamicin. This aminoglycoside resistance phenotype is new in enterococci. The genes conferring resistance to aminoglycosides and MLS antibiotics in this strain were carried on a plasmid, pIP810, that was self-transferable to to other Enterococcus strains. Resistance to tobramycin and structurally related aminoglycosides, kanamycin, neomycin, and dibekacin, was due to synthesis of a 4',4"-aminoglycoside nucleotidyltransferase. Homology was detected by hybridization between pIP810 DNA and a probe specific for a gene encoding an enzyme with identical site specificity in staphylococci. The bacteriostatic activity of amikacin apparently was not affected by the presence of the enzyme, although it was modified in vitro. However, the bactericidal activity of amikacin and the synergism of this aminoglycoside with penicillin were abolished.
Topics: Anti-Bacterial Agents; Culture Media; DNA, Bacterial; Drug Resistance, Microbial; Gene Expression Regulation, Bacterial; Gentamicins; Lactams; Microbial Sensitivity Tests; Nucleic Acid Hybridization; Nucleotidyltransferases; Penicillins; Phenotype; Plasmids; Streptococcus; Tobramycin
PubMed: 2171424
DOI: 10.1128/AAC.34.8.1565 -
The Journal of Antibiotics Aug 1982Streptomyces tenebrarius ISP 5477, which produces nebramycins, was highly resistant to the following aminoglycoside antibiotics: neamine, ribostamycin, butirosin A,...
Streptomyces tenebrarius ISP 5477, which produces nebramycins, was highly resistant to the following aminoglycoside antibiotics: neamine, ribostamycin, butirosin A, neomycin B, paromomycin, kanamycin A, dibekacin, gentamicin C complex, lividomycin A, istamycin B and streptomycin. Polyphenylalanine synthesis on the ribosomes of this strain was highly resistant to neamine, ribostamycin, butirosin A, kanamycins A, B and C, dibekacin, gentamicin C complex and istamycin B, moderately resistant to lividomycin A and streptomycin, but sensitive to neomycin B and paromomycin. Moreover, cell free extract of the strain contained phosphotransferase and N-acetyltransferase. The former enzyme was confirmed to be an aminoglycoside 6-phosphotransferase which inactivated streptomycin; the latter inactivated kanamycins B and C, dibekacin, neamine, neomycin B, paromomycin, lividomycin A, butirosin A and ribostamycin, but did not inactivate kanamycin A, gentamicin C complex and sagamicin, suggesting an aminoglycoside 2'-acetyltransferase. These results indicated that the high resistance of S. tenebrarius ISP 5477 to a wide range of aminoglycoside antibiotics is due to ribosomal resistance and to the inactivating enzymes, aminoglycoside N-acetyltransferase(s) and aminoglycoside 6-phosphotransferase.
Topics: Acetyltransferases; Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Microbial; Nebramycin; Phosphorylation; Ribosomes; Streptomyces
PubMed: 7142002
DOI: 10.7164/antibiotics.35.1020 -
Antimicrobial Agents and Chemotherapy Dec 2012The kanamycins form an important subgroup of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside antibiotics, comprising kanamycin A, kanamycin B, tobramycin, and...
The kanamycins form an important subgroup of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside antibiotics, comprising kanamycin A, kanamycin B, tobramycin, and dibekacin. These compounds interfere with protein synthesis by targeting the ribosomal decoding A site, and they differ in the numbers and locations of amino and hydroxy groups of the glucopyranosyl moiety (ring I). We synthesized kanamycin analogues characterized by subtle variations of the 2' and 6' substituents of ring I. The functional activities of the kanamycins and the synthesized analogues were investigated (i) in cell-free translation assays on wild-type and mutant bacterial ribosomes to study drug-target interaction, (ii) in MIC assays to assess antibacterial activity, and (iii) in rabbit reticulocyte translation assays to determine activity on eukaryotic ribosomes. Position 2' forms an intramolecular H bond with O5 of ring II, helping the relative orientations of the two rings with respect to each other. This bond becomes critical for drug activity when a 6'-OH substituent is present.
Topics: Amines; Animals; Anti-Bacterial Agents; Carbohydrate Sequence; Hydroxylation; Kanamycin; Luciferases; Microbial Sensitivity Tests; Models, Molecular; Molecular Sequence Data; Mutation; Mycobacterium smegmatis; RNA, Bacterial; RNA, Ribosomal; Rabbits; Reticulocytes; Ribosomes; Structure-Activity Relationship
PubMed: 22948879
DOI: 10.1128/AAC.01326-12 -
Antimicrobial Agents and Chemotherapy Sep 1980The pharmacokinetics of dibekacin, a new aminoglycoside antibiotic, was studied in volunteers given the same dose (100 mg) intramuscularly on two separate occasions and...
The pharmacokinetics of dibekacin, a new aminoglycoside antibiotic, was studied in volunteers given the same dose (100 mg) intramuscularly on two separate occasions and intravenously at two different rates of infusion. The kinetic parameters (t 1/2, 2.24 h, and Vd, 0.136 liter/kg, as the overall mean) observed after intramuscular administration appear to be compatible with those of other aminoglycosides and fairly reproducible within the same individuals. Dibekacin was rapidly absorbed (tmax, 0.84 h), yielding a peak level of 10.4 microgram/ml after the 100-mg intramuscular dose. After the 30- or 60-min infusion, the concentrations of dibekacin in serum fell bi-exponentially, giving an elimination half-life (t 1/2 beta) of 2.50 to 2.88 h. The highest serum levels after th 30- and 60-min infusions were 15.2 +/- 0.9 and 12.1 +/- 1.8 microgram/ml, respectively. Serum levels at 6 h after completion of infusions were 1.9 +/- 0.3 and 1.7 +/- 0.4 microgram/ml, respectively.
Topics: Adult; Bacillus subtilis; Dibekacin; Humans; Injections, Intramuscular; Injections, Intravenous; Kanamycin; Kinetics; Male; Middle Aged
PubMed: 6775594
DOI: 10.1128/AAC.18.3.372 -
The Journal of Antimicrobial... Aug 2017Mycobacterium abscessus is innately resistant to a variety of drugs thereby limiting therapeutic options. Bacterial resistance to aminoglycosides (AGs) is conferred...
OBJECTIVES
Mycobacterium abscessus is innately resistant to a variety of drugs thereby limiting therapeutic options. Bacterial resistance to aminoglycosides (AGs) is conferred mainly by AG-modifying enzymes, which often have overlapping activities. Several putative AG-modifying enzymes are encoded in the genome of M. abscessus . The aim of this study was to investigate the molecular basis underlying AG resistance in M. abscessus .
METHODS
M. abscessus deletion mutants deficient in one of three genes potentially involved in AG resistance, aac(2 ' ) , eis1 and eis2 , were generated by targeted gene inactivation, as were combinatorial double and triple deletion mutants. MICs were determined to study susceptibility to a variety of AG drugs and to capreomycin.
RESULTS
Deletion of aac(2 ' ) increased susceptibility of M. abscessus to kanamycin B, tobramycin, dibekacin and gentamicin C. Deletion of eis2 increased susceptibility to capreomycin, hygromycin B, amikacin and kanamycin B. Deletion of eis1 did not affect drug susceptibility. Equally low MICs of apramycin, arbekacin, isepamicin and kanamycin A for WT and mutant strains indicate that these drugs are not inactivated by either AAC(2 ' ) or Eis enzymes.
CONCLUSIONS
M. abscessus expresses two distinct AG resistance determinants, AAC(2 ' ) and Eis2, which confer clinically relevant drug resistance.
Topics: Aminoglycosides; Antibiotics, Antitubercular; Capreomycin; Drug Resistance, Bacterial; Gene Deletion; Genes, Bacterial; Microbial Sensitivity Tests; Mycobacterium abscessus
PubMed: 28486671
DOI: 10.1093/jac/dkx125 -
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 Jul 2000Daptomycin, a lipopeptide antibiotic, has broad activity against gram-positive organisms, similar to vancomycin; however, its mechanism of action differs, resulting in...
In vitro activities of daptomycin, arbekacin, vancomycin, and gentamicin alone and/or in combination against glycopeptide intermediate-resistant Staphylococcus aureus in an infection model.
Daptomycin, a lipopeptide antibiotic, has broad activity against gram-positive organisms, similar to vancomycin; however, its mechanism of action differs, resulting in interference with cell membrane transport and a more rapid bactericidal activity. In light of increasing need for alternative treatments against intermediate-resistant Staphylococcus aureus, there is revitalized interest in this antibiotic. We, therefore, evaluated the activity of daptomycin alone or in combination in an in vitro infection model against two glycopeptide intermediate-resistant S. aureus (GISA) isolates. Newly designed regimens of daptomycin at 4 and 6 mg/kg of body weight every 24 h (q24h) were compared to the previous regimen of 3 mg/kg q12h. Daptomycin MICs and minimal bactericidal concentrations (MBCs) (MIC/MBC) for Mu-50, HIP5836 (992), and MRSA-67 were 0.5/1.0, 0.5/1.0, and 0.125/0.5 microgram/ml, respectively. MICs and MBCs of arbekacin for the three strains were 2.0/8.0, 0. 125/0.5, and 0.125/0.25 microgram/ml, respectively. Vancomycin and gentamicin MICs and MBCs for the three strains were 8.0/8.0, 8.0/8.0, and 0.5/1.0 microgram/ml and 128/128, 0.5/1.0, and 0.25/0.5 microgram/ml, respectively. Our experience with daptomycin in an in vitro infection model has shown significant kill against the two GISA strains (Mu-50 and 992) (P < 0.03). We also noted that kill was related to a total dose effect for 992, in which simulated daptomycin in vivo dosages of 6 mg/kg q24h and 3 mg/kg q12h produced similar kill and 4 mg/kg q24h resulted in significant regrowth (P = 0.05). Combination therapy with arbekacin resulted in synergistic activity against Mu-50. Daptomycin area under the concentration-time curve/MIC and C(max)/MIC ranges for GISA isolates were 80 to 116 and 6 to 12, respectively, and ranges for MRSA-67 were 320 to 461 and 24 to 48, respectively, and appeared to have an association with kill (i.e., decreased CFU/milliliter) at 24 and 48 h. Therefore, these experiments suggest that daptomycin alone or in combination could provide an alternative for the treatment of GISA.
Topics: Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Dibekacin; Drug Resistance, Microbial; Drug Therapy, Combination; Gentamicins; Humans; Microbial Sensitivity Tests; Models, Biological; Staphylococcal Infections; Staphylococcus aureus; Vancomycin
PubMed: 10858356
DOI: 10.1128/AAC.44.7.1925-1929.2000