title: Novel quorum-quenching agents promote methicillin-resistant Staphylococcus aureus (MRSA) wound healing and sensitize MRSA to β-lactam antibiotics.
abstract: The dwindling repertoire of antibiotics to treat methicillin-resistant Staphylococcus aureus (MRSA) calls for novel treatment options. Quorum-quenching agents offer an alternative or an adjuvant to antibiotic therapy. Three biaryl hydroxyketone compounds discovered previously (F1, F12, and F19; G. Yu, D. Kuo, M. Shoham, and R. Viswanathan, ACS Comb Sci 16:85-91, 2014) were tested for efficacy in MRSA-infected animal models. Topical therapy of compounds F1 and F12 in a MRSA murine wound infection model promotes wound healing compared to the untreated control. Compounds F1, F12, and F19 afford significant survival benefits in a MRSA insect larva model. Combination therapy of these quorum-quenching agents with cephalothin or nafcillin, antibiotics to which MRSA is resistant in monotherapy, revealed additional survival benefits. The quorum-quenching agents sensitize MRSA to the antibiotic by a synergistic mode of action that also is observed in vitro. An adjuvant of 1 μg/ml F1, F12, or F19 reduces the MIC of nafcillin and cephalothin about 50-fold to values comparable to those for vancomycin, the antibiotic often prescribed for MRSA infections. These findings suggest that it is possible to resurrect obsolete antibiotic therapies in combination with these novel quorum-quenching agents.
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kuo
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Guanping
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Wyatt
authors.initials: W
authors.lastname: Hoch
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Gabay
authors.affiliation: Center for Medical Mycology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Long
authors.affiliation: Center for Medical Mycology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, USA.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ghannoum
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Nagy
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Viswanathan
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA mxs10@case.edu.
authors.forename: Menachem
authors.initials: M
authors.lastname: Shoham
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D002512:Cephalothin / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009254:Nafcillin / Q000494:pharmacology; D053038:Quorum Sensing / Q000187:drug effects*; D014945:Wound Healing / Q000187:drug effects*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D009254:Nafcillin; D002512:Cephalothin