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 language | English |
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Article number | 893 |
Pages (from-to) | 1-11 |
Number of pages | 11 |
Journal | Biomolecules |
Volume | 10 |
Issue number | 6 |
DOIs | |
Publication status | Published - 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