Unraveling the antitrypanosomal mechanism of benznidazole and related 2-nitroimidazoles: From prodrug activation to DNA damage.
Activation, Metabolic
/ physiology
DNA Breaks, Double-Stranded
/ drug effects
DNA Repair
/ drug effects
Genome, Protozoan
/ drug effects
Nitroimidazoles
/ pharmacology
Nitroreductases
/ metabolism
Prodrugs
/ chemistry
Trypanocidal Agents
/ pharmacology
Trypanosoma brucei brucei
/ drug effects
Trypanosomiasis, African
/ drug therapy
CRISPR gene editing
DNA repair
benznidazole
fluorescence profiling
gene deletion
prodrug activation
Journal
Molecular microbiology
ISSN: 1365-2958
Titre abrégé: Mol Microbiol
Pays: England
ID NLM: 8712028
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
17
05
2021
received:
03
02
2021
accepted:
29
05
2021
pubmed:
2
6
2021
medline:
29
12
2021
entrez:
1
6
2021
Statut:
ppublish
Résumé
Nitroheterocycles represent an important class of compound used to treat trypanosomiasis. They often function as prodrugs and can undergo type I nitroreductase (NTR1)-mediated activation before promoting their antiparasitic activities although the nature of these downstream effects has yet to be determined. Here, we show that in an NTR1-dependent process, benznidazole promotes DNA damage in the nuclear genome of Trypanosoma brucei, providing the first direct link between activation of this prodrug and a downstream trypanocidal mechanism. Phenotypic and protein expression studies revealed that components of the trypanosome's homologous recombination (HR) repair pathway (TbMRE11, γH2A, TbRAD51) cooperate to resolve the benznidazole-induced damage, indicating that the prodrug-induced lesions are most likely double stand DNA breaks, while the sequence/recruitment kinetics of these factors parallels that in other eukaryotes HR systems. When extended to other NTR1-activated 2-nitroimidazoles, some were shown to promote DNA damage. Intriguingly, the lesions induced by these required TbMRE11 and TbCSB activities to fix leading us to postulate that TbCSB may operate in systems other than the transcription-coupled nucleotide excision repair pathway. Understanding how existing trypanosomal drugs work will aid future drug design and help unlock novel reactions/pathways that could be exploited as targets for therapeutic intervention.
Substances chimiques
Nitroimidazoles
0
Prodrugs
0
Trypanocidal Agents
0
Nitroreductases
EC 1.7.-
benzonidazole
YC42NRJ1ZD
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
674-689Informations de copyright
© 2021 John Wiley & Sons Ltd.
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