Novel quorum-quenching agents promote methicillin-resistant Staphylococcus aureus (MRSA) wound healing and sensitize MRSA to β-lactam antibiotics

• Published in: Antimicrobial agents and chemotherapy Vol. 59; no. 3; pp. 1512 - 1518
• Main Authors: Kuo, David, Yu, Guanping, Hoch, Wyatt, Gabay, Dean, Long, Lisa, Ghannoum, Mahmoud, Nagy, Nancy, Harding, Clifford V, Viswanathan, Rajesh, Shoham, Menachem
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.03.2015
• Subjects: Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; beta-Lactams; beta-Lactams - pharmacology; Cell Line; Cephalothin - pharmacology; Experimental Therapeutics; Macrophages - immunology; Methicillin-Resistant Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus - drug effects; Mice; Microbial Sensitivity Tests; Nafcillin - pharmacology; Quorum Sensing; Quorum Sensing - drug effects; Staphylococcus aureus; Wound Healing; Wound Healing - drug effects
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.04767-14

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.