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

doi:10.1016/j.virol.2020.09.004

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

Virology. 2021 Jan 2:552:94-106. doi: 10.1016/j.virol.2020.09.004. Epub 2020 Oct 1.

Authors

Stacey L P Scroggs¹, Jordan T Gass², Ramesh Chinnasamy³, Steven G Widen⁴, Sasha R Azar⁵, Shannan L Rossi⁶, Jeffrey B Arterburn³, Nikos Vasilakis⁷, Kathryn A Hanley²

Affiliations

¹ Department of Biology, New Mexico State University, Las Cruces, NM, USA. Electronic address: stacey.scroggs@nih.gov.
² Department of Biology, New Mexico State University, Las Cruces, NM, USA.
³ Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, USA.
⁴ Department of Biochemistry & Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
⁵ Department of Pathology, The University of University of Texas Medical Branch, Galveston, TX, USA.
⁶ Department of Pathology, The University of University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, The University of University of Texas Medical Branch, Galveston, TX, USA.
⁷ Department of Pathology, The University of University of Texas Medical Branch, Galveston, TX, USA; Center for Biodefense and Emerging Infectious Diseases, The University of University of Texas Medical Branch, Galveston, TX, USA; Center for Tropical Diseases, The University of University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, The University of University of Texas Medical Branch, Galveston, TX, USA.

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.

Keywords: Antiviral; Ciprofloxacin; Dengue virus; Difloxacin; Enoxacin; Evolution; Fitness; Fluoroquinolone; Mechanism-of-action; Resistance.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptation, Biological
Animals
Antiviral Agents / pharmacology
Biological Evolution*
Cell Line
Chlorocebus aethiops
Ciprofloxacin / analogs & derivatives
Ciprofloxacin / pharmacology
Dengue / virology*
Dengue Virus / drug effects*
Dengue Virus / physiology*
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*

Substances

Antiviral Agents
Fluoroquinolones
Enoxacin
Ciprofloxacin
difloxacin

Abstract

Publication types

MeSH terms

Substances

Grants and funding