Small molecule MarR modulators potentiate ...
Type de document :
Article dans une revue scientifique: Article original
PMID :
URL permanente :
Titre :
Small molecule MarR modulators potentiate metronidazole antibiotic activity in aerobic E. coli by inducing activation by the nitroreductase NfsA.
Auteur(s) :
Caradec, Thibault [Auteur]
Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Ple, Coline [Auteur]
Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Sicoli, Giuseppe [Auteur]
Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement (LASIRE) - UMR 8516
Petrov, Ravil [Auteur]
Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Pradel, Elizabeth [Auteur]
Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
Sobieski, Cécilia [Auteur]
Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Antoine, Rudy [Auteur]
Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Orio, Maylis [Auteur]
Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement (LASIRE) - UMR 8516
Herledan, Adrien [Auteur]
Médicaments et Molécules pour agir sur les Systèmes Vivants (M2SV) - U1177
Willand, nicolas [Auteur]
Médicaments et Molécules pour agir sur les Systèmes Vivants (M2SV) - U1177
Hartkoorn, Ruben [Auteur]
Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Ple, Coline [Auteur]

Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Sicoli, Giuseppe [Auteur]

Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement (LASIRE) - UMR 8516
Petrov, Ravil [Auteur]
Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Pradel, Elizabeth [Auteur]

Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
Sobieski, Cécilia [Auteur]
Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Antoine, Rudy [Auteur]

Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Orio, Maylis [Auteur]

Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement (LASIRE) - UMR 8516
Herledan, Adrien [Auteur]
Médicaments et Molécules pour agir sur les Systèmes Vivants (M2SV) - U1177
Willand, nicolas [Auteur]

Médicaments et Molécules pour agir sur les Systèmes Vivants (M2SV) - U1177
Hartkoorn, Ruben [Auteur]

Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
Titre de la revue :
J Biol Chem
Nom court de la revue :
J Biol Chem
Pagination :
107431
Date de publication :
2024-06-08
ISSN :
1083-351X
Mot(s)-clé(s) en anglais :
E. coli
antibiotic
antibiotic action
boosting
drug action
enzyme mechanism
metronidazole
nitroreductase
radical
transcription regulation
antibiotic
antibiotic action
boosting
drug action
enzyme mechanism
metronidazole
nitroreductase
radical
transcription regulation
Discipline(s) HAL :
Chimie/Chimie théorique et/ou physique
Résumé en anglais : [en]
Antibiotic resistant Enterobacterales pose a major threat to healthcare systems worldwide, necessitating the development of novel strategies to fight such hard-to-kill bacteria. One potential approach is to develop molecules ...
Lire la suite >Antibiotic resistant Enterobacterales pose a major threat to healthcare systems worldwide, necessitating the development of novel strategies to fight such hard-to-kill bacteria. One potential approach is to develop molecules that force bacteria to hyper-activate prodrug antibiotics, thus rendering them more effective. In the present work, we aimed to obtain proof-of-concept data to support that small molecules targeting transcriptional regulators can potentiate the antibiotic activity of the prodrug metronidazole (MTZ) against Escherichia coli under aerobic conditions. By screening a chemical library of small molecules a series of structurally related molecules were identified that had little inherent antibiotic activity, but showed substantial activity in combination with ineffective concentrations of MTZ. Transcriptome analyses, functional genetics, thermal shift assays and electrophoretic mobility shift assays were then used to demonstrate that these MTZ boosters target the transcriptional repressor MarR, resulting in the up-regulation of the marRAB operon and its downstream MarA regulon. The associated upregulation of the flavin-containing nitro-reductase; NfsA was then shown to be critical for the booster mediated potentiation of MTZ antibiotic activity. Transcriptomic studies, biochemical assays and electron paramagnetic resonance measurements were then used to show that under aerobic conditions, NfsA catalyzed 1-electron reduction of MTZ to the MTZ radical anion which in turn induced lethal DNA damage in E. coli. This work reports the first example of prodrug boosting in Enterobacterales by transcriptional modulators and highlights that MTZ antibiotic activity can be chemically induced under anaerobic growth conditions.Lire moins >
Lire la suite >Antibiotic resistant Enterobacterales pose a major threat to healthcare systems worldwide, necessitating the development of novel strategies to fight such hard-to-kill bacteria. One potential approach is to develop molecules that force bacteria to hyper-activate prodrug antibiotics, thus rendering them more effective. In the present work, we aimed to obtain proof-of-concept data to support that small molecules targeting transcriptional regulators can potentiate the antibiotic activity of the prodrug metronidazole (MTZ) against Escherichia coli under aerobic conditions. By screening a chemical library of small molecules a series of structurally related molecules were identified that had little inherent antibiotic activity, but showed substantial activity in combination with ineffective concentrations of MTZ. Transcriptome analyses, functional genetics, thermal shift assays and electrophoretic mobility shift assays were then used to demonstrate that these MTZ boosters target the transcriptional repressor MarR, resulting in the up-regulation of the marRAB operon and its downstream MarA regulon. The associated upregulation of the flavin-containing nitro-reductase; NfsA was then shown to be critical for the booster mediated potentiation of MTZ antibiotic activity. Transcriptomic studies, biochemical assays and electron paramagnetic resonance measurements were then used to show that under aerobic conditions, NfsA catalyzed 1-electron reduction of MTZ to the MTZ radical anion which in turn induced lethal DNA damage in E. coli. This work reports the first example of prodrug boosting in Enterobacterales by transcriptional modulators and highlights that MTZ antibiotic activity can be chemically induced under anaerobic growth conditions.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
Université de Lille
CNRS
CNRS
Collections :
Équipe(s) de recherche :
Propriétés magnéto structurales des matériaux (PMSM)
Date de dépôt :
2024-06-13T21:01:53Z
2024-06-26T06:37:02Z
2024-06-26T06:37:02Z