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...
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doaj-696d0b2389534c178208a6e6c5ba2f892021-09-27T06:33:27ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2021-09-011210.3389/fmicb.2021.698468698468relA Inactivation Converts Sulfonamides Into Bactericidal CompoundsLizhen Si0Lizhen Si1Jing Gu2Mi Wen3Mi Wen4Ruiqi Wang5Ruiqi Wang6Joy Fleming7Jinyue Li8Jintian Xu9Jintian Xu10Lijun Bi11Lijun Bi12Lijun Bi13Jiaoyu Deng14Jiaoyu Deng15Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaKey Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of RNA Biology and National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaKey Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of RNA Biology and National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaSchool of Stomatology and Medicine, Foshan University, Foshan, ChinaGuangdong Province Key Laboratory of TB Systems Biology and Translational Medicine, Foshan, ChinaKey Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaGuangdong Province Key Laboratory of TB Systems Biology and Translational Medicine, Foshan, ChinaFolates 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.https://www.frontiersin.org/articles/10.3389/fmicb.2021.698468/fullsulfonamidesRelAreactive oxygen speciesferrous ionDNA double-strand breaksbactericidal effects |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lizhen Si Lizhen Si Jing Gu Mi Wen Mi Wen Ruiqi Wang Ruiqi Wang Joy Fleming Jinyue Li Jintian Xu Jintian Xu Lijun Bi Lijun Bi Lijun Bi Jiaoyu Deng Jiaoyu Deng |
spellingShingle |
Lizhen Si Lizhen Si Jing Gu Mi Wen Mi Wen Ruiqi Wang Ruiqi Wang Joy Fleming Jinyue Li Jintian Xu Jintian Xu Lijun Bi Lijun Bi Lijun Bi Jiaoyu Deng Jiaoyu Deng relA Inactivation Converts Sulfonamides Into Bactericidal Compounds Frontiers in Microbiology sulfonamides RelA reactive oxygen species ferrous ion DNA double-strand breaks bactericidal effects |
author_facet |
Lizhen Si Lizhen Si Jing Gu Mi Wen Mi Wen Ruiqi Wang Ruiqi Wang Joy Fleming Jinyue Li Jintian Xu Jintian Xu Lijun Bi Lijun Bi Lijun Bi Jiaoyu Deng Jiaoyu Deng |
author_sort |
Lizhen Si |
title |
relA Inactivation Converts Sulfonamides Into Bactericidal Compounds |
title_short |
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_sort |
rela inactivation converts sulfonamides into bactericidal compounds |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Microbiology |
issn |
1664-302X |
publishDate |
2021-09-01 |
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. |
topic |
sulfonamides RelA reactive oxygen species ferrous ion DNA double-strand breaks bactericidal effects |
url |
https://www.frontiersin.org/articles/10.3389/fmicb.2021.698468/full |
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