Enhancement of Fluoride’s Antibacterial and Antibiofilm Effects against Oral Staphylococcus aureus by the Urea Derivative BPU

<b>Background:</b> The oral cavity is an important but often overlooked reservoir for <i>Staphylococcus aureus</i>. The effective control and prevention of <i>S. aureus</i> colonization and infection in the oral and maxillofacial regions are crucial for public health. Fluoride is widely used in dental care for its remineralization and antibacterial properties. However, its effectiveness against <i>S. aureus</i> has not been thoroughly investigated. <b>Objectives:</b> This study aimed to evaluate the potential of combining sodium fluoride (NaF) with compounds to enhance its antibacterial and antibiofilm effects against <i>S. aureus</i>. <b>Method:</b> We found that a urea derivative significantly enhances the efficacy of fluoride by promoting the retention of fluoride ions within the cells. The synergistic antibacterial and antibiofilm effects of BPU with NaF were confirmed through various assays, including checkerboard assays, time-kill assays, and growth curve analysis. These findings were further supported by additional methods, including transmission electron microscopy (TEM), in silico simulations, and gene overexpression studies. <b>Results:</b> These findings suggest that targeting fluoride ion membrane exporters could enhance antibacterial efficacy. When combined with fluoride, 1,3-Bis [3,5-bis(trifluoromethyl)phenyl]urea (BPU) showed increased effectiveness in inhibiting <i>S. aureus</i> growth and reducing established biofilms. <b>Conclusions:</b> This novel combination represents a promising therapeutic strategy for treating biofilm-associated <i>S. aureus</i> infections, offering a new strategy in oral healthcare. To fully evaluate the clinical potential of this synergistic therapy, further in vivo studies are essential.