Development of 6′-N-acylated isepamicin analogs with improved antibacterial activity against isepamicin-resistant pathogens

Yeon Hee Ban, Myoung Chong Song, Hee Jin Kim, Heejeong Lee, Jae Bok Wi, Je Won Park, Dong Gun Lee, Yeo Joon Yoon

Research output: Contribution to journalArticle

Abstract

The development of new aminoglycoside (AG) antibiotics has been required to overcome the resistance mechanism of AG-modifying enzymes (AMEs) of AG-resistant pathogens. The AG acetyltransferase, AAC(6′)-APH(2″), one of the most typical AMEs, exhibiting substrate promiscuity towards a variety of AGs and acyl-CoAs, was employed to enzymatically synthesize new 6′-N-acylated isepamicin (ISP) analogs, 6′-N-acetyl/-propionyl/-malonyl ISPs. They were all active against the ISP-resistant Gram-negative bacteria tested, and the 6′-N-acetyl ISP displayed reduced toxicity compared to ISP in vitro. This study demonstrated the importance of the modification of the 6′-amino group in circumventing AG-resistance and the potential of regioselective enzymatic modification of AG scaffolds for the development of more robust AG antibiotics.

Original languageEnglish
Article number893
Pages (from-to)1-11
Number of pages11
JournalBiomolecules
Volume10
Issue number6
DOIs
Publication statusPublished - 2020 Jun

Keywords

  • 6′-N-acylation
  • Antibacterial activity
  • Cytotoxicity
  • Enzymatic synthesis
  • Isepamicin analogs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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