Chemo-enzymatic Synthesis of Pseudo-trisaccharide Aminoglycoside Antibiotics with Enhanced Nonsense Read-through Inducer Activity.
ChemMedChem
; 18(1): e202200497, 2023 01 03.
Article
em En
| MEDLINE
| ID: mdl-36259357
ABSTRACT
Aminoglycosides (AGs) are broad-spectrum antibiotics used to treat bacterial infections. Over the last two decades, studies have reported the potential of AGs in the treatment of genetic disorders caused by nonsense mutations, owing to their ability to induce the ribosomes to read through these mutations and produce a full-length protein. However, the principal limitation in the clinical application of AGs arises from their high toxicity, including nephrotoxicity and ototoxicity. In this study, five novel pseudo-trisaccharide analogs were synthesized by chemo-enzymatic synthesis by acid hydrolysis of commercially available AGs, followed by an enzymatic reaction using recombinant substrate-flexible KanM2 glycosyltransferase. The relationships between their structures and biological activities, including the antibacterial, nephrotoxic, and nonsense readthrough inducer (NRI) activities, were investigated. The absence of 1-N-acylation, 3',4'-dideoxygenation, and post-glycosyl transfer modifications on the third sugar moiety of AGs diminishes their antibacterial activities. The 3',4'-dihydroxy and 6'-hydroxy moieties regulate the inâ
vitro nephrotoxicity of AGs in mammalian cell lines. The 3',4'-dihydroxy and 6'-methyl scaffolds are indispensable for the ex vivo NRI activity of AGs. Based on the alleviated inâ
vitro antibacterial properties and nephrotoxicity, and the highest ex vivo NRI activity among the five compounds, a kanamycin analog (6'-methyl-3''-deamino-3''-hydroxykanamycin C) was selected as a novel AG hit for further studies on human genetic disorders caused by premature transcriptional termination.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trissacarídeos
/
Códon sem Sentido
Limite:
Animals
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Humans
Idioma:
En
Revista:
ChemMedChem
Assunto da revista:
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2023
Tipo de documento:
Article