Abstract
This study elucidated the role of boeravinone B, a NorA multidrug efflux pump inhibitor, in biofilm inhibition. The effects of boeravinone B plus ciprofloxacin, a NorA substrate, were evaluated in NorA-overexpressing, wild-type, and knocked-out Staphylococcus aureus (SA-1199B, SA-1199, and SA-K1758, respectively). The mechanism of action was confirmed using the ethidium bromide accumulation and efflux assay. The role of boeravinone B as a human P-glycoprotein (P-gp) inhibitor was examined in the LS-180 (colon cancer) cell line. Moreover, its role in the inhibition of biofilm formation and intracellular invasion of S. aureus in macrophages was studied. Boeravinone B reduced the minimum inhibitory concentration (MIC) of ciprofloxacin against S. aureus and its methicillin-resistant strains; the effect was stronger in SA-1199B. Furthermore, time–kill kinetics revealed that boeravinone B plus ciprofloxacin, at subinhibitory concentration (0.25 × MIC), is as equipotent as that at the MIC level. This combination also had a reduced mutation prevention concentration. Boeravinone B reduced the efflux of ethidium bromide and increased the accumulation, thus strengthening the role as a NorA inhibitor. Biofilm formation was reduced by four–eightfold of the minimal biofilm inhibitory concentration of ciprofloxacin, effectively preventing bacterial entry into macrophages. Boeravinone B effectively inhibited P-gp with half maximal inhibitory concentration (IC50) of 64.85 μM. The study concluded that boeravinone B not only inhibits the NorA-mediated efflux of fluoroquinolones but also considerably inhibits the biofilm formation of S. aureus. Its P-gp inhibition activity demonstrates its potential as a bioavailability and bioefficacy enhancer.
Highlights
The development of multidrug resistance (MDR) upon chronic exposure to chemotherapeutic agents is considered the major reason for the failure of chemotherapy in cancer and infectious diseases (Poole, 2005; Leitner et al, 2011; Joshi et al, 2014)
We described the role of boeravinone B in ciprofloxacin potentiating activity against NorA-overexpressing strains of S. aureus and P-gp inhibition in the colon cancer cell line
Minimum effective concentration (MEC) of boeravinone B was determined which is defined as concentration at which there is atleast fourfold reductions in minimum inhibitory concentration (MIC) of ciprofloxacin
Summary
The development of multidrug resistance (MDR) upon chronic exposure to chemotherapeutic agents is considered the major reason for the failure of chemotherapy in cancer and infectious diseases (Poole, 2005; Leitner et al, 2011; Joshi et al, 2014). Efflux pumps are transmembrane proteins, which are the major contributors to multidrug resistance (MDR) in patients with cancer and infectious diseases. NorA, an established multidrug efflux pump model in S. aureus, accounts for extruding quinolones, quaternary ammonium salts, acridines, rhodamines, verapamil, and ethidium bromide (Kaatz et al, 2003; Khan et al, 2006; Leitner et al, 2011; Tegos et al, 2011; Holler et al, 2012; Schindler et al, 2013; Fontaine et al, 2015; Tintino et al, 2016). A recently published comprehensive review summarized the applications of nanoparticles are being explored for efflux inhibitory activity in addition to biofilm inhibition (Gupta et al, 2017)
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