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

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

4 Scopus citations

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
State	Published - Jun 2020

Keywords

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

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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 = "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",

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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

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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U2 - 10.3390/biom10060893

DO - 10.3390/biom10060893

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SN - 2218-273X

VL - 10

SP - 1

EP - 11

JO - Biomolecules

JF - Biomolecules

IS - 6

M1 - 893

ER -

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

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