Cargando…
Redirecting an Anticancer to an Antibacterial Hit Against Methicillin-Resistant Staphylococcus aureus
YM155 is a clinically evaluated anticancer with a fused naphthoquinone-imidazolium scaffold. In this study, we demonstrated that based on weak or cryptic antibacterial activity of YM155 against methicillin-resistant Staphylococcus aureus (MRSA) (MIC of 50 μg/ml), some congeneric compounds with short...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398426/ https://www.ncbi.nlm.nih.gov/pubmed/30858845 http://dx.doi.org/10.3389/fmicb.2019.00350 |
_version_ | 1783399580600107008 |
---|---|
author | Jang, Hye-Jeong Chung, In-Young Lim, Changjin Chung, Sungkyun Kim, Bi-o Kim, Eun Sook Kim, Seok-Ho Cho, You-Hee |
author_facet | Jang, Hye-Jeong Chung, In-Young Lim, Changjin Chung, Sungkyun Kim, Bi-o Kim, Eun Sook Kim, Seok-Ho Cho, You-Hee |
author_sort | Jang, Hye-Jeong |
collection | PubMed |
description | YM155 is a clinically evaluated anticancer with a fused naphthoquinone-imidazolium scaffold. In this study, we demonstrated that based on weak or cryptic antibacterial activity of YM155 against methicillin-resistant Staphylococcus aureus (MRSA) (MIC of 50 μg/ml), some congeneric compounds with short alkyl chains (e.g., c5 with a hexyl chain) at the N3 position of the scaffold, displayed more potent antibacterial activity against MRSA (MIC of 3.13 μg/ml), which is in a clinically achievable range. Their antibacterial activity was evident against Gram-negative bacteria, only in the presence of the outer membrane-permeabilizing agent, polymyxin B. The antibacterial efficacy of c5 was confirmed using the Drosophila systemic infection model. We also characterized five spontaneous c5-resistant MRSA mutants that carry mutations in the ubiE gene, for quinone metabolism and respiratory electron transfer, and subsequently exhibited reduced respiration activity. The antibacterial activity of c5 was compromised either by an antioxidant, N-acetylcysteine, or in an anaerobic condition. These suggest that the antibacterial mechanism of c5 involves the generation of reactive oxygen species (ROS), presumably during respiratory electron transport. This study provides an insight into “drug redirecting,” through a chemical modification, based on an ROS-generating pharmacophore. |
format | Online Article Text |
id | pubmed-6398426 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-63984262019-03-11 Redirecting an Anticancer to an Antibacterial Hit Against Methicillin-Resistant Staphylococcus aureus Jang, Hye-Jeong Chung, In-Young Lim, Changjin Chung, Sungkyun Kim, Bi-o Kim, Eun Sook Kim, Seok-Ho Cho, You-Hee Front Microbiol Microbiology YM155 is a clinically evaluated anticancer with a fused naphthoquinone-imidazolium scaffold. In this study, we demonstrated that based on weak or cryptic antibacterial activity of YM155 against methicillin-resistant Staphylococcus aureus (MRSA) (MIC of 50 μg/ml), some congeneric compounds with short alkyl chains (e.g., c5 with a hexyl chain) at the N3 position of the scaffold, displayed more potent antibacterial activity against MRSA (MIC of 3.13 μg/ml), which is in a clinically achievable range. Their antibacterial activity was evident against Gram-negative bacteria, only in the presence of the outer membrane-permeabilizing agent, polymyxin B. The antibacterial efficacy of c5 was confirmed using the Drosophila systemic infection model. We also characterized five spontaneous c5-resistant MRSA mutants that carry mutations in the ubiE gene, for quinone metabolism and respiratory electron transfer, and subsequently exhibited reduced respiration activity. The antibacterial activity of c5 was compromised either by an antioxidant, N-acetylcysteine, or in an anaerobic condition. These suggest that the antibacterial mechanism of c5 involves the generation of reactive oxygen species (ROS), presumably during respiratory electron transport. This study provides an insight into “drug redirecting,” through a chemical modification, based on an ROS-generating pharmacophore. Frontiers Media S.A. 2019-02-25 /pmc/articles/PMC6398426/ /pubmed/30858845 http://dx.doi.org/10.3389/fmicb.2019.00350 Text en Copyright © 2019 Jang, Chung, Lim, Chung, Kim, Kim, Kim and Cho. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Jang, Hye-Jeong Chung, In-Young Lim, Changjin Chung, Sungkyun Kim, Bi-o Kim, Eun Sook Kim, Seok-Ho Cho, You-Hee Redirecting an Anticancer to an Antibacterial Hit Against Methicillin-Resistant Staphylococcus aureus |
title | Redirecting an Anticancer to an Antibacterial Hit Against Methicillin-Resistant Staphylococcus aureus |
title_full | Redirecting an Anticancer to an Antibacterial Hit Against Methicillin-Resistant Staphylococcus aureus |
title_fullStr | Redirecting an Anticancer to an Antibacterial Hit Against Methicillin-Resistant Staphylococcus aureus |
title_full_unstemmed | Redirecting an Anticancer to an Antibacterial Hit Against Methicillin-Resistant Staphylococcus aureus |
title_short | Redirecting an Anticancer to an Antibacterial Hit Against Methicillin-Resistant Staphylococcus aureus |
title_sort | redirecting an anticancer to an antibacterial hit against methicillin-resistant staphylococcus aureus |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398426/ https://www.ncbi.nlm.nih.gov/pubmed/30858845 http://dx.doi.org/10.3389/fmicb.2019.00350 |
work_keys_str_mv | AT janghyejeong redirectingananticancertoanantibacterialhitagainstmethicillinresistantstaphylococcusaureus AT chunginyoung redirectingananticancertoanantibacterialhitagainstmethicillinresistantstaphylococcusaureus AT limchangjin redirectingananticancertoanantibacterialhitagainstmethicillinresistantstaphylococcusaureus AT chungsungkyun redirectingananticancertoanantibacterialhitagainstmethicillinresistantstaphylococcusaureus AT kimbio redirectingananticancertoanantibacterialhitagainstmethicillinresistantstaphylococcusaureus AT kimeunsook redirectingananticancertoanantibacterialhitagainstmethicillinresistantstaphylococcusaureus AT kimseokho redirectingananticancertoanantibacterialhitagainstmethicillinresistantstaphylococcusaureus AT choyouhee redirectingananticancertoanantibacterialhitagainstmethicillinresistantstaphylococcusaureus |