Prostaglandin E 2 Receptor Antagonist with Antimicrobial Activity against Methicillin-Resistant Staphylococcus aureus

• Published in: Antimicrobial agents and chemotherapy 2018-03, Vol.62 (3)
• Main Authors: Ikeh, Mélanie A C, Fidel, Jr, Paul L, Noverr, Mairi C
• Format: Article
• Language: English
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01920-17

Polymicrobial intra-abdominal infections (IAI) involving and are associated with severe morbidity and mortality (∼80%). Our laboratory discovered that the immunomodulatory eicosanoid prostaglandin E (PGE ) plays a key role in the lethal inflammatory response during polymicrobial IAI using a mouse model of infection. In studies designed to uncover key PGE biosynthesis/signaling components involved in the response, selective eicosanoid enzyme inhibitors and receptor antagonists were selected and prescreened for antimicrobial activity against or Unexpectedly, we found that the EP receptor antagonist L-161,982 had direct growth-inhibitory effects on at the physiological concentration required to block the PGE interaction with EP This antimicrobial activity was observed with methicillin-sensitive and methicillin-resistant (MRSA) strains, with the MIC and minimum bactericidal concentration values for planktonic cells being 50 μg/ml and 100 μg/ml, respectively. In addition, L-161,982 inhibited biofilm formation and had activity against preformed mature biofilms. More importantly, treatment of mice with L-161,982 following intraperitoneal inoculation with a lethal dose of MRSA significantly reduced the bioburden and enhanced survival. Furthermore, L-161,982 protected mice against the synergistic lethality induced by coinfection with and The antimicrobial activity of L-161,982 is independent of EP receptor inhibitory activity; an alternative EP receptor antagonist exerted no antimicrobial or protective effects. Taken together, these findings demonstrate that L-161,982 has potent antimicrobial activity against MRSA and may represent a significant therapeutic alternative in improving the prognosis of mono- or polymicrobial infections involving MRSA.