Development of 6′-<i>N</i>-Acylated Isepamicin Analogs with Improved Antibacterial Activity Against Isepamicin-Resistant Pathogens

• Main Authors: Yeon Hee Ban, Myoung Chong Song, Hee Jin Kim, Heejeong Lee, Jae Bok Wi, Je Won Park, Dong Gun Lee, Yeo Joon Yoon
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Biomolecules
• Subjects: isepamicin analogs; 6′-<i>N</i>-acylation; enzymatic synthesis; antibacterial activity; cytotoxicity
• Online Access: https://www.mdpi.com/2218-273X/10/6/893
• ISSN: 2218-273X

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′-<i>N</i>-acylated isepamicin (ISP) analogs, 6′-<i>N</i>-acetyl/-propionyl/-malonyl ISPs. They were all active against the ISP-resistant Gram-negative bacteria tested, and the 6′-<i>N</i>-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.