Benzodioxane-benzamides as promising inhibitors of Escherichia coli FtsZ.
1,4-Benzodioxane-benzamides
Antimicrobial resistance
Bacterial division
FtsZ assembly
Gram-negative bacteria
In vitro and in vivo
Journal
International journal of biological macromolecules
ISSN: 1879-0003
Titre abrégé: Int J Biol Macromol
Pays: Netherlands
ID NLM: 7909578
Informations de publication
Date de publication:
31 Dec 2023
31 Dec 2023
Historique:
received:
23
05
2023
revised:
02
08
2023
accepted:
16
08
2023
medline:
27
11
2023
pubmed:
28
8
2023
entrez:
27
8
2023
Statut:
ppublish
Résumé
The conserved process of cell division in bacteria has been a long-standing target for antimicrobials, although there are few examples of potent broad-spectrum compounds that inhibit this process. Most currently available compounds acting on division are directed towards the FtsZ protein, a self-assembling GTPase that is a central element of the division machinery in most bacteria. Benzodioxane-benzamides are promising candidates, but poorly explored in Gram-negatives. We have tested a number of these compounds on E. coli FtsZ and found that many of them significantly stabilized the polymers against disassembly and reduced the GTPase activity. Reconstitution in crowded cell-like conditions showed that FtsZ bundles were also susceptible to these compounds, including some compounds that were inactive on protofilaments in dilute conditions. They efficiently killed E. coli cells defective in the AcrAB efflux pump. The activity of the compounds on cell growth and division generally showed a good correlation with their effect in vitro, and our experiments are consistent with FtsZ being the target in vivo. Our results uncover the detrimental effects of benzodioxane-benzamides on permeable E. coli cells via its central division protein, implying that lead compounds may be found within this class for the development of antibiotics against Gram-negative bacteria.
Identifiants
pubmed: 37634788
pii: S0141-8130(23)03294-4
doi: 10.1016/j.ijbiomac.2023.126398
pii:
doi:
Substances chimiques
Bacterial Proteins
0
Benzamides
0
Cytoskeletal Proteins
0
GTP Phosphohydrolases
EC 3.6.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
126398Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Silvia Zorrilla reports financial support was provided by Spanish Ministerio de Ciencia e Innovación. Marta Sobrinos-Sanguino reports financial support was provided by Agencia Estatal de Investigación and the European Social Fund. William Margolin reports financial support was provided by National Institutes of Health.