Semisynthetic aminoglycoside antibiotics: Development and enzymatic modifications

@article{Kondo1999SemisyntheticAA,
  title={Semisynthetic aminoglycoside antibiotics: Development and enzymatic modifications},
  author={Shinichi Kondo and Kunimoto Hotta},
  journal={Journal of Infection and Chemotherapy},
  year={1999},
  volume={5},
  pages={1-9}
}
  • S. Kondo, K. Hotta
  • Published 1999
  • Chemistry, Biology
  • Journal of Infection and Chemotherapy
Abstract The critical resistance mechanisms of aminoglycoside antibiotics in bacteria of clinical importance are the enzymatic N-acetylation, O-phosphorylation, and O-nucleotidylation that generally result in the inactivation of aminoglycosides. To overcome such resistance mechanisms, dibekacin (3′,4′-dideoxykanamycin B) was developed as the first rationally designed semisynthetic aminoglycoside, based on the enzymatic 3′-O-phosphorylation of kanamycin. Subsequently, amikacin, netilmicin, and… 

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References

SHOWING 1-10 OF 50 REFERENCES

The novel enzymatic 3''-N-acetylation of arbekacin by an aminoglycoside 3-N-acetyltransferase of Streptomyces origin and the resulting activity.

The results illuminated a novel aspect of arbekacin distinct from the other aminoglycosides, which showed antibiotic activity as high as that of 2'-N-acetylarbekacin reported previously, whereas 3"-N-acetylamikacin showed no substantial activity.

Enzymatic 2'-N-acetylation of arbekacin and antibiotic activity of its product.

It is believed 2'-N-acetyl ABK has the highest and broadest antibacterial activity, compared with known N- acetylated AGs.

New 2''-amino derivatives of arbekacin, potent aminoglycoside antibiotics against methicillin-resistant Staphylococcus aureus.

Replacement of the 2"-hydroxyl group by amino group in ABKor in dibekacin (DKB, 3',4'-dideoxykanamycin B) was designed to obtain potent derivatives against MRSA.

Synthesis of 3'-deoxykanamycin effective against kanamycin-resistant Escherichia coli and Pseudomonas aeruginosa.

The authors attempted, for the first approach, to prepare 3r-0-methylkanamycin (I) by a synthetic method, and suggested that blocking or removal of the hydroxyl group which is phosphorylated will give new compounds effective against the resistant organisms.

BB-K 8, a new semisynthetic aminoglycoside antibiotic.

BB-K8 is a new derivative of kanamycin acylated with L(-)-γ-γ-amino-α-hydroxybutyric acid at the C-1 amino group of the 2-deoxystreptamine moiety that has antibacterial activity generally equal to Kanamycin againstkanamycin-sensitive organisms and is also active against kan amycin- and/or gentamicin-resistant organisms, including Pseudomonas strains.

Biochemical mechanism of resistance to aminoglycosidic antibiotics.

  • H. Umezawa
  • Chemistry, Biology
    Advances in carbohydrate chemistry and biochemistry
  • 1974

Antibacterial activity and nephrotoxicity of two novel 2″-amino derivatives of arbekacin

Results indicate that the 2″-amino group introduced to ABK confers high stabilization to the aminoglycoside-modifying enzymes, while reducing acute and renal toxicities.

A newly recognized acetylated metabolite of arbekacin in arbekacin-resistant strains of methicillin-resistant Staphylococcus aureus.

A newly recognized metabolite of arbekacin in arbekACin-resistant strains of MRSA is described, which is shown to be the bifunctional aminoglycoside-modifying enzyme, aminglycoside phosphotransferase (APH(2 ))–aminoglycosid acetyltransferase (AAC(6 )), which simultaneously phosphorylates and acetylates.

Tobramycin adenylyltransferase: a new aminoglycoside-inactivating enzyme from Staphylococcus epidermidis.

Certain strains of Staphylococcus epidermidis resistant to the aminoglycoside antibiotics were shown to contain an enzyme that inactivates the kanamycins, neomycins, butirosins, paromomycin,

3',4'-dideoxy-kanamycin B active against kanamycin-resistant Escherichia coli and Pseudomonas aeruginosa.

synthetic method showed antibacterial activity against E. colt 1629, 1630 carrying R factor and P. aeruginosa for which kanamycin showed no activity. In this communication, the application of a