Development of 6′-<i>N</i>-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
Affiliations
Yeon Hee Ban
Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul 08826, Korea
Myoung Chong Song
Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul 08826, Korea
Hee Jin Kim
Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Korea
Heejeong Lee
School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daehakro 80, Bukgu, Daegu 41566, Korea
Jae Bok Wi
Department of Integrated Biomedical and Life Sciences, Korea University, Seoul 02841, Korea
Je Won Park
Department of Integrated Biomedical and Life Sciences, Korea University, Seoul 02841, Korea
Dong Gun Lee
School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daehakro 80, Bukgu, Daegu 41566, Korea
Yeo Joon Yoon
Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul 08826, Korea
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.
