Evolution of resistance to fluoroquinolones by dengue virus serotype 4 provides insight into mechanism of action and consequences for viral fitness.
Adaptation, Biological
Animals
Antiviral Agents
/ pharmacology
Biological Evolution
Cell Line
Chlorocebus aethiops
Ciprofloxacin
/ analogs & derivatives
Dengue
/ virology
Dengue Virus
/ drug effects
Drug Resistance, Viral
Enoxacin
/ pharmacology
Fluoroquinolones
/ pharmacology
Genetic Fitness
/ drug effects
HEK293 Cells
Host Microbial Interactions
Humans
Mutation
Vero Cells
Viral Envelope
/ physiology
Virus Physiological Phenomena
/ drug effects
Antiviral
Ciprofloxacin
Dengue virus
Difloxacin
Enoxacin
Evolution
Fitness
Fluoroquinolone
Mechanism-of-action
Resistance
Journal
Virology
ISSN: 1096-0341
Titre abrégé: Virology
Pays: United States
ID NLM: 0110674
Informations de publication
Date de publication:
02 01 2021
02 01 2021
Historique:
received:
07
05
2020
revised:
30
08
2020
accepted:
08
09
2020
pubmed:
30
10
2020
medline:
31
12
2021
entrez:
29
10
2020
Statut:
ppublish
Résumé
Drugs against flaviviruses such as dengue (DENV) and Zika (ZIKV) virus are urgently needed. We previously demonstrated that three fluoroquinolones, ciprofloxacin, enoxacin, and difloxacin, suppress replication of six flaviviruses. To investigate the barrier to resistance and mechanism(s) of action of these drugs, DENV-4 was passaged in triplicate in HEK-293 cells in the presence or absence of each drug. Resistance to ciprofloxacin was detected by the seventh passage and to difloxacin by the tenth, whereas resistance to enoxacin did not occur within ten passages. Two putative resistance-conferring mutations were detected in the envelope gene of ciprofloxacin and difloxacin-resistant DENV-4. In the absence of ciprofloxacin, ciprofloxacin-resistant viruses sustained a significantly higher viral titer than control viruses in HEK-293 and HuH-7 cells and resistant viruses were more stable than control viruses at 37 °C. These results suggest that the mechanism of action of ciprofloxacin and difloxacin involves interference with virus binding or entry.
Identifiants
pubmed: 33120225
pii: S0042-6822(20)30188-4
doi: 10.1016/j.virol.2020.09.004
pmc: PMC7528753
pii:
doi:
Substances chimiques
Antiviral Agents
0
Fluoroquinolones
0
Enoxacin
325OGW249P
Ciprofloxacin
5E8K9I0O4U
difloxacin
5Z7OO9FNFD
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
94-106Subventions
Organisme : NIAID NIH HHS
ID : R21 AI092041
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI115577
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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