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

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

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 a...

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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
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spelling doaj-5419bf9e8ca947d4826c840b65c889db2020-11-25T03:11:51ZengMDPI AGBiomolecules2218-273X2020-06-011089389310.3390/biom10060893Development of 6′-<i>N</i>-Acylated Isepamicin Analogs with Improved Antibacterial Activity Against Isepamicin-Resistant PathogensYeon Hee Ban0Myoung Chong Song1Hee Jin Kim2Heejeong Lee3Jae Bok Wi4Je Won Park5Dong Gun Lee6Yeo Joon Yoon7Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul 08826, KoreaNatural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul 08826, KoreaDepartment of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, KoreaSchool of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daehakro 80, Bukgu, Daegu 41566, KoreaDepartment of Integrated Biomedical and Life Sciences, Korea University, Seoul 02841, KoreaDepartment of Integrated Biomedical and Life Sciences, Korea University, Seoul 02841, KoreaSchool of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daehakro 80, Bukgu, Daegu 41566, KoreaNatural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul 08826, KoreaThe 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.https://www.mdpi.com/2218-273X/10/6/893isepamicin analogs6′-<i>N</i>-acylationenzymatic synthesisantibacterial activitycytotoxicity
collection DOAJ
language English
format Article
sources DOAJ
author Yeon Hee Ban
Myoung Chong Song
Hee Jin Kim
Heejeong Lee
Jae Bok Wi
Je Won Park
Dong Gun Lee
Yeo Joon Yoon
spellingShingle Yeon Hee Ban
Myoung Chong Song
Hee Jin Kim
Heejeong Lee
Jae Bok Wi
Je Won Park
Dong Gun Lee
Yeo Joon Yoon
Development of 6′-<i>N</i>-Acylated Isepamicin Analogs with Improved Antibacterial Activity Against Isepamicin-Resistant Pathogens
Biomolecules
isepamicin analogs
6′-<i>N</i>-acylation
enzymatic synthesis
antibacterial activity
cytotoxicity
author_facet Yeon Hee Ban
Myoung Chong Song
Hee Jin Kim
Heejeong Lee
Jae Bok Wi
Je Won Park
Dong Gun Lee
Yeo Joon Yoon
author_sort Yeon Hee Ban
title Development of 6′-<i>N</i>-Acylated Isepamicin Analogs with Improved Antibacterial Activity Against Isepamicin-Resistant Pathogens
title_short Development of 6′-<i>N</i>-Acylated Isepamicin Analogs with Improved Antibacterial Activity Against Isepamicin-Resistant Pathogens
title_full Development of 6′-<i>N</i>-Acylated Isepamicin Analogs with Improved Antibacterial Activity Against Isepamicin-Resistant Pathogens
title_fullStr Development of 6′-<i>N</i>-Acylated Isepamicin Analogs with Improved Antibacterial Activity Against Isepamicin-Resistant Pathogens
title_full_unstemmed Development of 6′-<i>N</i>-Acylated Isepamicin Analogs with Improved Antibacterial Activity Against Isepamicin-Resistant Pathogens
title_sort development of 6′-<i>n</i>-acylated isepamicin analogs with improved antibacterial activity against isepamicin-resistant pathogens
publisher MDPI AG
series Biomolecules
issn 2218-273X
publishDate 2020-06-01
description 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.
topic isepamicin analogs
6′-<i>N</i>-acylation
enzymatic synthesis
antibacterial activity
cytotoxicity
url https://www.mdpi.com/2218-273X/10/6/893
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AT heejinkim developmentof6iniacylatedisepamicinanalogswithimprovedantibacterialactivityagainstisepamicinresistantpathogens
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