Old Drugs with New Tricks: Efficacy of Fluoroquinolones to Suppress Replication of Flaviviruses

Abstract

Repurposing FDA-approved compounds could provide the fastest route to alleviate the burden of disease caused by flaviviruses. In this study, three fluoroquinolones, enoxacin, difloxacin and ciprofloxacin, curtailed replication of flaviviruses Zika (ZIKV), dengue (DENV), Langat (LGTV) and Modoc (MODV) in HEK-293 cells at low micromolar concentrations. Time-of-addition assays suggested that enoxacin suppressed ZIKV replication at an intermediate step in the virus life cycle, whereas ciprofloxacin and difloxacin had a wider window of efficacy. A129 mice infected with 1 × 105 plaque-forming units (pfu) ZIKV FSS13025 (n = 20) or phosphate buffered saline (PBS) (n = 11) on day 0 and treated with enoxacin at 10 mg/kg or 15 mg/kg or diluent orally twice daily on days 1–5 did not differ in weight change or virus titer in serum or brain. However, mice treated with enoxacin showed a significant, five-fold decrease in ZIKV titer in testes relative to controls. Mice infected with 1 × 102 pfu ZIKV (n = 13) or PBS (n = 13) on day 0 and treated with 15 mg/kg oral enoxacin or diluent twice daily pre-treatment and days 1–5 post-treatment also did not differ in weight and viral load in the serum, brain, and liver, but mice treated with enoxacin showed a significant, 2.5-fold decrease in ZIKV titer in testes relative to controls. ZIKV can be sexually transmitted, so reduction of titer in the testes by enoxacin should be further investigated.

Fluoroquinolone Antibiotics Exhibit Low Antiviral Activity against SARS-CoV-2 and MERS-CoV

“…The cell types used in this study were Vero cells, African green monkey kidney cells that are interferon-deficient [ 31 , 32 ], and A549 human lung cells that have been engineered to overexpress the SARS-CoV-2 entry receptor ACE2. As has been documented previously, fluoroquinolone antiviral potency likely varies by cell type and level of cellular differentiation [ 12 , 14 ].…”

“…Fluoroquinolones are known to suppress the replication of RNA viruses such as dengue, Zika, and hepatitis C viruses [ 12 , 13 , 14 , 15 , 16 ]. The antiviral mechanisms of action are not fully understood, but have been suggested to include interference with viral entry and the inhibition of the viral helicase [ 12 , 13 , 15 ]. Several fluoroquinolones have been identified in large antiviral screens or molecular docking analyses as possibly interfering with the SARS-CoV-2 infectious cycle.…”

“…The fluoroquinolones evaluated in this study were enoxacin (Alfa Aesar, Tewksbury, MA, USA), ciprofloxacin (Sigma-Aldrich, St. Louis, MO, USA), levofloxacin (Sigma-Aldrich, St. Louis, MO, USA), and moxifloxacin (Sigma-Aldrich, St. Louis, MO, USA) ( Figure S1 ). The drugs were prepared as previously described [ 12 ]. Briefly, the ciprofloxacin, levofloxacin, and moxifloxacin were solubilized in millipure water to 1.5 mM.…”

“…The fluoroquinolone toxicity for Vero and A549/ACE2 cells was evaluated based on the methods used to evaluate fluoroquinolone toxicity in human embryonic kidney cells (HEK-293) [ 12 ]. Briefly, 8 × 10 4 cells per well were plated onto a tissue culture-treated 96-well plate, with one plate per cell type.…”

“…Fluoroquinolones are broad-spectrum antibiotics [ 11 ] that have also demonstrated antiviral potency against multiple positive-sense, single-stranded RNA viruses, such as dengue virus [ 12 , 13 ], Zika virus [ 12 , 13 , 14 ], hepatitis C virus [ 15 ], and rhinovirus [ 16 ], but the mechanism of action has not been fully elucidated. In response to the COVID-19 pandemic, fluoroquinolones have been suggested as a potential repurposed therapy to treat infection with SARS-CoV-2 [ 17 , 18 , 19 , 20 ].…”