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

• Type of Material: Article
• Authors: Cassandra Quave, Emory University; Miriam Estévez-Carmona, University of Arkansas for Medical Sciences; Cesar M. Compadre, University of Arkansas for Medical Sciences; Gerren Hobby, University of Arkansas for Medical Sciences; Howard Hendrickson, University of Arkansas for Medical Sciences; Karen E. Beenken, University of Arkansas for Medical Sciences; Mark S. Smeltzer, University of Arkansas for Medical Sciences
• Language: English
• Date: 2012-01-05
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2012 Quave et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0028737
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 7
• Issue: 1
• Start Page: e28737
• End Page: e28737
• Grant/Funding Information: This work was supported by an F32 Fellowship to CQ (AT005040) from the National Center for Complementary and Alternative Medicine (NCCAM) and by a grant from the Department of the Army USAMRAA to MSS (OR090571). Support was also obtained from resources provided through the Clinical and Translational Sciences Award (RR0298884) to the University of Arkansas for Medical Sciences.
• Keywords: Bacterial biofilms; Catheters; MEDICINAL-PLANTS; Science & Technology; HYPERICUM; PHENOTYPE; EXPRESSION; Kidneys; Biofilms; Coatings; Staphylococcus aureus; Plasma proteins; SARA; GLYCOSIDES; Antibiotics; EXTRACTS; HEALTH; Multidisciplinary Sciences
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Immunology

Abstract

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.