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relA Inactivation Converts Sulfonamides Into Bactericidal Compounds
Folates are required for the de novo biosynthesis of purines, thymine, methionine, glycine, and pantothenic acid, key metabolites that bacterial cells cannot survive without. Sulfonamides, which inhibit bacterial folate biosynthesis and are generally considered as bacteriostats, have been extensivel...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503649/ https://www.ncbi.nlm.nih.gov/pubmed/34646242 http://dx.doi.org/10.3389/fmicb.2021.698468 |
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author | Si, Lizhen Gu, Jing Wen, Mi Wang, Ruiqi Fleming, Joy Li, Jinyue Xu, Jintian Bi, Lijun Deng, Jiaoyu |
author_facet | Si, Lizhen Gu, Jing Wen, Mi Wang, Ruiqi Fleming, Joy Li, Jinyue Xu, Jintian Bi, Lijun Deng, Jiaoyu |
author_sort | Si, Lizhen |
collection | PubMed |
description | Folates are required for the de novo biosynthesis of purines, thymine, methionine, glycine, and pantothenic acid, key metabolites that bacterial cells cannot survive without. Sulfonamides, which inhibit bacterial folate biosynthesis and are generally considered as bacteriostats, have been extensively used as broad-spectrum antimicrobials for decades. Here we show that, deleting relA in Escherichia coli and other bacterial species converted sulfamethoxazole from a bacteriostat into a bactericide. Not as previously assumed, the bactericidal effect of SMX was not caused by thymine deficiency. When E. coli ∆relA was treated with SMX, reactive oxygen species and ferrous ion accumulated inside the bacterial cells, which caused extensive DNA double-strand breaks without the involvement of incomplete base excision repair. In addition, sulfamethoxazole showed bactericidal effect against E. coli O157 ∆relA in mice, suggesting the possibility of designing new potentiators for sulfonamides targeting RelA. Thus, our study uncovered the previously unknown bactericidal effects of sulfonamides, which advances our understanding of their mechanisms of action, and will facilitate the designing of new potentiators for them. |
format | Online Article Text |
id | pubmed-8503649 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85036492021-10-12 relA Inactivation Converts Sulfonamides Into Bactericidal Compounds Si, Lizhen Gu, Jing Wen, Mi Wang, Ruiqi Fleming, Joy Li, Jinyue Xu, Jintian Bi, Lijun Deng, Jiaoyu Front Microbiol Microbiology Folates are required for the de novo biosynthesis of purines, thymine, methionine, glycine, and pantothenic acid, key metabolites that bacterial cells cannot survive without. Sulfonamides, which inhibit bacterial folate biosynthesis and are generally considered as bacteriostats, have been extensively used as broad-spectrum antimicrobials for decades. Here we show that, deleting relA in Escherichia coli and other bacterial species converted sulfamethoxazole from a bacteriostat into a bactericide. Not as previously assumed, the bactericidal effect of SMX was not caused by thymine deficiency. When E. coli ∆relA was treated with SMX, reactive oxygen species and ferrous ion accumulated inside the bacterial cells, which caused extensive DNA double-strand breaks without the involvement of incomplete base excision repair. In addition, sulfamethoxazole showed bactericidal effect against E. coli O157 ∆relA in mice, suggesting the possibility of designing new potentiators for sulfonamides targeting RelA. Thus, our study uncovered the previously unknown bactericidal effects of sulfonamides, which advances our understanding of their mechanisms of action, and will facilitate the designing of new potentiators for them. Frontiers Media S.A. 2021-09-27 /pmc/articles/PMC8503649/ /pubmed/34646242 http://dx.doi.org/10.3389/fmicb.2021.698468 Text en Copyright © 2021 Si, Gu, Wen, Wang, Fleming, Li, Xu, Bi and Deng. https://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 Si, Lizhen Gu, Jing Wen, Mi Wang, Ruiqi Fleming, Joy Li, Jinyue Xu, Jintian Bi, Lijun Deng, Jiaoyu relA Inactivation Converts Sulfonamides Into Bactericidal Compounds |
title | relA Inactivation Converts Sulfonamides Into Bactericidal Compounds |
title_full | relA Inactivation Converts Sulfonamides Into Bactericidal Compounds |
title_fullStr | relA Inactivation Converts Sulfonamides Into Bactericidal Compounds |
title_full_unstemmed | relA Inactivation Converts Sulfonamides Into Bactericidal Compounds |
title_short | relA Inactivation Converts Sulfonamides Into Bactericidal Compounds |
title_sort | rela inactivation converts sulfonamides into bactericidal compounds |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503649/ https://www.ncbi.nlm.nih.gov/pubmed/34646242 http://dx.doi.org/10.3389/fmicb.2021.698468 |
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