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 journalArticlepeer-review

    4 Citations (Scopus)

    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

    Bibliographical note

    Funding Information:
    Funding: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Ministry of Science and ICT (2019R1A2B5B03069338: Y.J.Y.; 2020R1A2C2008061: J.W.P.; 2020R1A2B5B01001905: D.G.L.) and the Ministry of Education (2019R1I1A1A01062130: Y.H.B.). This research was also supported by the Cooperative Research Program for Agriculture Science and Technology Development (PJ01316001: M.C.S.) by the Rural Development Administration, Republic of Korea.

    Publisher Copyright:
    © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

    Keywords

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

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology

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