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Open AccessArticle

Development of 6′-N-Acylated Isepamicin Analogs with Improved Antibacterial Activity against Isepamicin-Resistant Pathogens

1
Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul 08826, Korea
2
Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Korea
3
School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daehakro 80, Bukgu, Daegu 41566, Korea
4
Department of Integrated Biomedical and Life Sciences, Korea University, Seoul 02841, Korea
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(6), 893; https://doi.org/10.3390/biom10060893
Received: 11 April 2020 / Revised: 28 May 2020 / Accepted: 9 June 2020 / Published: 11 June 2020
(This article belongs to the Special Issue Recent Advance of Actinomycetes)
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. View Full-Text
Keywords: isepamicin analogs; 6′-N-acylation; enzymatic synthesis; antibacterial activity; cytotoxicity isepamicin analogs; 6′-N-acylation; enzymatic synthesis; antibacterial activity; cytotoxicity
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MDPI and ACS Style

Ban, Y.H.; Song, M.C.; Kim, H.J.; Lee, H.; Wi, J.B.; Park, J.W.; Lee, D.G.; Yoon, Y.J. Development of 6′-N-Acylated Isepamicin Analogs with Improved Antibacterial Activity against Isepamicin-Resistant Pathogens. Biomolecules 2020, 10, 893.

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