Clinically Approved Drugs Inhibit the Staphylococcus aureus Multidrug NorA Efflux Pump and Reduce Biofilm Formation

Saskia Zimmermann; Mareike Klinger-Strobel; Jürgen A Bohnert; Sindy Wendler; Jürgen Rödel; Mathias W Pletz; Bettina Löffler; Lorena Tuchscherr

doi:10.3389/fmicb.2019.02762

Clinically Approved Drugs Inhibit the Staphylococcus aureus Multidrug NorA Efflux Pump and Reduce Biofilm Formation

Front Microbiol. 2019 Dec 3:10:2762. doi: 10.3389/fmicb.2019.02762. eCollection 2019.

Authors

Saskia Zimmermann^{1

2}, Mareike Klinger-Strobel³, Jürgen A Bohnert^{1

4}, Sindy Wendler¹, Jürgen Rödel¹, Mathias W Pletz³, Bettina Löffler^{1

2}, Lorena Tuchscherr^{1

2}

Affiliations

¹ Institute of Medical Microbiology, Jena University Hospital, Jena, Germany.
² Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
³ Institute of Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany.
⁴ Institute of Medical Microbiology, Greifswald University Hospital, Greifswald, Germany.

Abstract

Staphylococcus aureus has acquired resistance to antibiotics since their first use. The S. aureus protein NorA, an efflux pump belonging to the major facilitator superfamily (MFS), contributes to resistance to fluoroquinolones (e.g., ciprofloxacin), biocides, dyes, quaternary ammonium compounds, and antiseptics. Different compounds have been identified as potential efflux pump inhibitors (EPIs) of NorA that result in increased intracellular concentration of antibiotics, restoring their antibacterial activity and cell susceptibility. However, none of the currently known EPIs have been approved for clinical use, probably due to their toxicity profiles. In the present study, we screened approved drugs for possible efflux pump inhibition. By screening a compound library of approximately 1200 different drugs, we identified nilotinib, a tyrosine kinase inhibitor, as showing the best efflux pump inhibitory activity, with a fractional inhibitory concentration index of 0.1875, indicating synergism with ciprofloxacin, and a minimum effective concentration as low as 0.195 μM. Moreover, at 0.39 μM, nilotinib, in combination with 8 μg/mL of ciprofloxacin, led to a significant reduction in biofilm formation and preformed mature biofilms. This is the first description of an approved drug that can be used as an efflux pump inhibitor and to reduce biofilms formation at clinically achievable concentrations.

Keywords: NorA; S. aureus; biofilm; clinical drugs; multidrug resistance.