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A kanamycin-producing strain, Streptomyces kanamyceticus ISP5500, is resistant to kanamycin. A kanamycin resistance determinant was cloned from S. kanamyceticus into Streptomyces lividans 1326, using the plasmid vector pIJ702. The resulting plasmid, pMCP5, could also transform Streptomyces lavendulae S985 and Streptomyces parvulus 2283 to kanamycin resistance. Transformants carrying pMCP5 were markedly more resistant than S. kanamyceticus to the aminoglycoside antibiotics sisomicin, tobramycin, amikacin, and gentamicin. Studies in vitro polyphenylalanine synthesis showed that strains carrying pMCP5 contained kanamycin-resistant ribosomes. However, growing S. kanamyceticus contained kanamycin-sensitive ribosomes. Ribosomes from S. kanamyceticus grown under kanamycin-producing conditions were kanamycin resistant.
It has previously been shown that simple compounds with multiple amine groups are ototoxic, the degree of ototoxicity depending on the number of amine groups in the molecule. The relationship between the number of amino groups and ototoxicity in aminoglycoside was studied using kanamycin A and kanamycin B, which contain 4 and 5 amino groups respectively. Forty-five pigmented guinea pigs were injected intratympanically with 0.1 ml of different concentrations of kanamycin A and kanamycin B. The animals were sacrificed 4 days after injection and the organ of Corti was studied by scanning electron microscopy. It was found that on an equimolar basis, kanamycin B (with 5 amino groups) is more cochleotoxic than kanamycin A (with 4 amino groups). The greater cochleotoxic potential of kanamycin B may be explained by the higher cationic nature of the molecule due to protonation of the amino--NH2 groups at physiological pH, resulting in a greater affinity between the drug and the cell membrane.
The resistance development pattern of Mycobacterium smegmatis strain 17023 (Jucho) to streptomycin and kanamycin was studied. The medium used was Ogawa egg medium, and the level of resistance was determined for each clone derived from single colony by the 'actual count' method. Hence, the resistance level was estimated as the highest concentration of drugs, in which small inocula consisting of 20 to 100 colony-forming units could grow after seven days incubation. Only one type of resistance mutants resistant to more than 1,000 micrograms/ml streptomycin was isolated and these mutants were also resistant to 8 micrograms/ml kanamycin. On the other hand, only one type of kanamycin-resistant mutants resistant to 8 micrograms/ml kanamycin was isolated and these mutants were also resistant to more than 1,000 micrograms/ml streptomycin. Accordingly, there was a complete cross-resistance relationship between streptomycin and kanamycin resistances. Therefore, there existed only one phenotype, which is simultaneously resistant to streptomycin and kanamycin. The mutants occurred at a rate of about 2 x 10(-8) per viable bacterial population of the parent strain. Streptomycin-dependent mutants occurred at a rate of about 2 x 10(-9). The number of resistant phenotypes to streptomycin and kanamycin was only one in M. smegmatis, while it was five in M. tuberculosis and 2 or 3 in M. avium complex (Tsukamura, M. and Mizuno, S.: J. Gen. Microbiol. 88: 269-274, 1975; Tsukamura, M.: Kekkaku 62: 445-458, 1987). The simplicity of the resistance system of M. smegmatis suggests that this organism is evolutionally primitive in the world of mycobacteria.
A kanamycin producer, Streptomyces kanamyceticus IFO 13414 is highly resistant to kanamycin. Cloning of the kanamycin resistance genes in S. lividans 1326 with pIJ702 gave several kanamycin resistant transformants. Two transformants, S. lividans SNUS 90041 and S. lividans SNUS 91051 showed similar resistance patterns to various aminoglycoside antibiotics. Gene mapping experiments revealed that plasmids pSJ5030 and pSJ2131 isolated from the transformants have common resistant gene fragments. Subcloning of pSJ5030 gave a 1.8 Kb gene fragment which showed resistance to kanamycin. Cell free extracts of S. lividans SNUS 90041, S. lividans SNUS 91051 and subclone a S. lividans SNUS 91064 showed kanamycin acetyltransferase activity. The detailed gene map is included.
Clinical and experimental data indicate that aminoglycoside ototoxicity occurs more frequently in individuals previously exposed to ototoxic drugs. This study investigated the auditory effect of repetitive administration of kanamycin on newborn guinea pigs that had previously been exposed, in utero, to kanamycin administered to their mothers. Sixteen pregnant guinea pigs in the late stages of gestation were divided into two groups, one receiving kanamycin 500 mg/kg per day intramuscularly for 8 days, and the other acting as a control. After birth, the mothers and their newborns in both groups were examined for auditory brain stem response (ABR) and then treated with kanamycin 500mg/kg per day for 4 days. The results from the second examination demonstrated that the group receiving prior treatment with kanamycin, despite their good ABR responses during the first measurement, showed significantly elevated auditory thresholds compared to the control group. Therefore, any ototoxic drugs should be used with extreme caution in newborns having had prior exposure to the drugs in utero, even if they have a "normal" auditory response after birth.
It has been suggested that the aminoglycoside drugs are ototoxic because they contain amine groups that interact with membrane phospholipids. The interaction of kanamycin A and kanamycin B with vesicles containing various phospholipids was assessed from studies of vesicle aggregation and of the fluorescence of the probes 1-anilino-8-naphthalene sulfonic acid (ANS) and 1,6-diphenyl-1,3,5-hexatriene (DPH) added to the system. Kanamycin B, with 5 amino groups, showed a stronger interaction with the acidic phospholipids than kanamycin A, with only 4 amino groups. The evidence indicated that the interaction was an ionic one involving the charged groups of both components with penetration of the hydrocarbon interior of the bilayers. Of all the phospholipids tested polyphosphoinositide showed the greatest ability to interact with the kanamycins, supporting the proposal that interaction with this phospholipid may be the basis of the ototoxicity of aminoglycosides.
The previously cloned kanamycin resistance gene (kmr) from Streptomyces kanamyceticus ISP5500 was shown to modify the 30S ribosomal subunit in a subunit exchange experiment. The kmr gene, which was normally repressed in S. kanamyceticus, appeared to be induced under growth conditions which activated kanamycin biosynthesis. S1 mapping analysis revealed that the expression of the kmr gene was regulated at the transcriptional level. Acetylation of kanamycin is another resistance mechanism in the kanamycin producer. However, unlike kmr-mediated resistance, the enzyme which catalyzed acetylation was not regulated coordinately with kanamycin biosynthesis.
The emergence of kanamycin resistance in a polyamine-deficient mutant of E. coli transformed with a plasmid encoding the kanamycin phosphotransferase gene has been studied. The initial inhibition of growth and protein synthesis caused by the addition of the antibiotic could be reversed earlier in polyamine-supplemented bacteria than in those depleted of the organic bases. Concomitantly, we have observed that the increase of kanamycin phosphotransferase activity evoking the antibiotic resistance was higher in bacteria cultivated in the presence of putrescine. This result seems to depend exclusively on the enhanced capacity of the translation process in bacteria grown with polyamines since the transcription of phosphotransferase gene was higher in cells subjected to polyamine starvation.
A novel kanamycin phosphotransferase gene, aphA-7, was cloned from a 14-kb plasmid obtained from a strain of Campylobacter jejuni and the nucleotide sequence of the gene was determined. The presumed open reading frame of the aphA-7 structural gene was 753 bp in length and encoded a protein of 251 amino acids with a calculated weight of 29,691 Da. A 29-kDa protein was demonstrated in Escherichia coli maxicells containing the cloned aphA-7 gene. A ribosomal binding site corresponding to 5 of 8 bases of the 3' end of the E. coli 16S rRNA was 8 bp upstream of the start codon. Sequences corresponding to the -35 and -10 regions of the consensus promoter sequences of E. coli were upstream of the presumed initiation codon of the gene. The DNA sequence was most closely related to the aphA-3 gene from Streptococcus faecalis, showing 55.4% sequence similarity. There was 45.6% identity at the amino acid level between the aphA-3 and the aphA-7 proteins. Of the three conserved regions noted previously in phosphotransferase genes, the aphA-7 amino acid sequence was identical to the six conserved amino acids in motif 3, but differed in one of the five conserved amino acids in motif 1 (if gaps are permitted) and 3 of the 10 conserved residues in motif 2. The 32.8% G + C ratio in the open reading frame of the aphA-7 kanamycin resistance gene, which is similar to that of the C. jejuni chromosome, suggests that the aphA-7 may be indigenous to Campylobacters.
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.
Kanamycin B content in kanamycin preparations was determined with column chromatography and PMR spectroscopy. It was shown that coincidence of the results obtained with both the procedures in analysis of the preparations subjected to additional recrystallization was satisfactory. With the use of nonrecrystallized preparations the admixtures interfered with the results in using the developed procedure.
The absorption and retention of kanamycin by the pulmonary system was evaluated after aerosol administration to rats. Tissue level concentrations of the drug were assayed by the agar-plate bioassay method. Mean concentrations of 6.58 mug/g and 3.52 mug/g were found in the lung and kidney homogenates, respectively, 26 hr after the final exposure period. No detectable level was found in the plasma.
The effects of the interaction between kanamycin (KAN) and ethacrynic acid (EA) on the ultrastructure of the guinea pig cochlea were studied 3, 4, 6, and 24 hours following administration of EA (40 mg/kg) to animals pretreated 2 h earlier with KAN (400 mg/kg). Appropriate saline (SAL) controls were included giving 4 treatments: KAN/EA, KAN/SAL, SAL/EA and SAL/SAL. The outer hair cells of the organ of Corti showed nuclear and plasma membrane changes at 3 h and were completely destroyed at 24 h. The inner hair cells were unaffected. Severe swelling was seen in the stria vascularis of both KAN/EA and SAL/EA animals at 3 h and was gone by 24 h. KAN/EA had a greater effect on the stria than had SAL/EA. These results were consistent with the time course of the effect of the drugs on the a.c. and d.c. endocochlear potentials. KAN concentrations in perilymph were unaffected by treatment with EA.