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Background  Biofilms contribute to the pathogenesis of many forms of  Staphylococcus aureus  infection. Treatment of these infections is complicated by intrinsic resistance to conventional antibiotics, thus creating an urgent need for strategies that can be used for the prevention and treatment of biofilm-associated infections.    Methodology/Principal Findings  This study demonstrates that a botanical natural product composition (220D-F2) rich in ellagic acid and its derivatives can limit  S. aureus  biofilm formation to a degree that can be correlated with increased antibiotic susceptibility. The source of this composition is  Rubus ulmifolius  Schott. (Rosaceae), a plant used in complementary and alternative medicine in southern Italy for the treatment of skin and soft tissue infections. All  S. aureus  clonal lineages tested exhibited a reduced capacity to form a biofilm at 220D-F2 concentrations ranging from 50–200 µg/mL, which were well below the concentrations required to limit bacterial growth (530–1040 µg/mL). This limitation was therapeutically relevant in that inclusion of 220D-F2 resulted in enhanced susceptibility to the functionally-distinct antibiotics daptomycin, clindamycin and oxacillin. Testing with kidney and liver cell lines also demonstrated a lack of host cell cytotoxicity at concentrations of 220D-F2 required to achieve these effects.    Conclusions/Significance  These results demonstrate that extract 220D-F2 from the root of  Rubus ulmifolius  can be used to inhibit  S. aureus  biofilm formation to a degree that can be correlated with increased antibiotic susceptibility without toxic effects on normal mammalian cells. Hence, 220D-F2 is a strong candidate for development as a botanical drug for use in the prevention and treatment of  S. aureus  biofilm-associated infections.

Ellagic Acid Derivatives from Rubus ulmifolius Inhibit Staphylococcus aureus Biofilm Formation and Improve Response to Antibiotics