Evolution of resistance to fluoroquinolones by dengue virus serotype 4 provides insight into mechanism of action and consequences for viral fitness

Stacey L.P. Scroggs, Jordan T. Gass, Ramesh Chinnasamy, Steven G. Widen, Sasha R. Azar, Shannan L. Rossi, Jeffrey B. Arterburn, Nikos Vasilakis, Kathryn A. Hanley

    Research output: Contribution to journalArticlepeer-review

    5 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)94-106
    Number of pages13
    JournalVirology
    Volume552
    DOIs
    StatePublished - Jan 2 2021

    Keywords

    • Antiviral
    • Ciprofloxacin
    • Dengue virus
    • Difloxacin
    • Enoxacin
    • Evolution
    • Fitness
    • Fluoroquinolone
    • Mechanism-of-action
    • Resistance

    ASJC Scopus subject areas

    • Virology

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