Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Si, Lizhen, Gu, Jing, Wen, Mi, Wang, Ruiqi, Fleming, Joy, Li, Jinyue, Xu, Jintian, Bi, Lijun, Deng, Jiaoyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
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
_version_ 1784581172581367808
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
work_keys_str_mv AT silizhen relainactivationconvertssulfonamidesintobactericidalcompounds
AT gujing relainactivationconvertssulfonamidesintobactericidalcompounds
AT wenmi relainactivationconvertssulfonamidesintobactericidalcompounds
AT wangruiqi relainactivationconvertssulfonamidesintobactericidalcompounds
AT flemingjoy relainactivationconvertssulfonamidesintobactericidalcompounds
AT lijinyue relainactivationconvertssulfonamidesintobactericidalcompounds
AT xujintian relainactivationconvertssulfonamidesintobactericidalcompounds
AT bilijun relainactivationconvertssulfonamidesintobactericidalcompounds
AT dengjiaoyu relainactivationconvertssulfonamidesintobactericidalcompounds