Development of 6′-N-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

doi:10.3390/biom10060893

Development of 6′-N-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

School of Biosystem and Biomedical Science

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

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
Article number	893
Pages (from-to)	1-11
Number of pages	11
Journal	Biomolecules
Volume	10
Issue number	6
DOIs	https://doi.org/10.3390/biom10060893
Publication status	Published - 2020 Jun

Keywords

6′-N-acylation
Antibacterial activity
Cytotoxicity
Enzymatic synthesis
Isepamicin analogs

ASJC Scopus subject areas

Biochemistry
Molecular Biology

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10.3390/biom10060893

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@article{754c8503c56341d3b121a2b3ebd4c53c,

title = "Development of 6′-N-acylated isepamicin analogs with improved antibacterial activity against isepamicin-resistant pathogens",

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.",

keywords = "6′-N-acylation, Antibacterial activity, Cytotoxicity, Enzymatic synthesis, Isepamicin analogs",

author = "Ban, {Yeon Hee} and Song, {Myoung Chong} and Kim, {Hee Jin} and Heejeong Lee and Wi, {Jae Bok} and Park, {Je Won} and Lee, {Dong Gun} and Yoon, {Yeo Joon}",

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: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = jun,

doi = "10.3390/biom10060893",

language = "English",

volume = "10",

pages = "1--11",

journal = "Biomolecules",

issn = "2218-273X",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

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T1 - Development of 6′-N-acylated isepamicin analogs with improved antibacterial activity against isepamicin-resistant pathogens

AU - Ban, Yeon Hee

AU - Song, Myoung Chong

AU - Kim, Hee Jin

AU - Lee, Heejeong

AU - Wi, Jae Bok

AU - Park, Je Won

AU - Lee, Dong Gun

AU - Yoon, Yeo Joon

N1 - 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.

PY - 2020/6

Y1 - 2020/6

N2 - 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.

AB - 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.

KW - 6′-N-acylation

KW - Antibacterial activity

KW - Cytotoxicity

KW - Enzymatic synthesis

KW - Isepamicin analogs

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ER -

Development of 6′-N-acylated isepamicin analogs with improved antibacterial activity against isepamicin-resistant pathogens

Abstract

Keywords

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