Prostaglandin E2 Receptor Antagonist with Antimicrobial Activity against Methicillin-Resistant Staphylococcus aureus
| Autor: | Mairi C. Noverr, Paul L. Fidel, Mélanie A. C. Ikeh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Methicillin-Resistant Staphylococcus aureus Staphylococcus aureus Prostaglandin E2 receptor 030106 microbiology EP4 Receptor Microbial Sensitivity Tests Peritonitis medicine.disease_cause Microbiology 03 medical and health sciences Mice Anti-Infective Agents Candida albicans Medicine Animals Pharmacology (medical) Experimental Therapeutics Pharmacology Minimum bactericidal concentration biology business.industry Receptors Prostaglandin E EP2 Subtype Antimicrobial biology.organism_classification Methicillin-resistant Staphylococcus aureus Corpus albicans Anti-Bacterial Agents Infectious Diseases Biofilms lipids (amino acids peptides and proteins) Female business Receptors Prostaglandin E EP4 Subtype |
| Popis: | Polymicrobial intra-abdominal infections (IAI) involving Candida albicans and Staphylococcus aureus are associated with severe morbidity and mortality (∼80%). Our laboratory discovered that the immunomodulatory eicosanoid prostaglandin E 2 (PGE 2 ) 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 2 biosynthesis/signaling components involved in the response, selective eicosanoid enzyme inhibitors and receptor antagonists were selected and prescreened for antimicrobial activity against C. albicans or S. aureus . Unexpectedly, we found that the EP 4 receptor antagonist L-161,982 had direct growth-inhibitory effects on S. aureus in vitro at the physiological concentration required to block the PGE 2 interaction with EP 4 . This antimicrobial activity was observed with methicillin-sensitive S. aureus and methicillin-resistant S. aureus (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 S. aureus 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 C. albicans and S. aureus . The antimicrobial activity of L-161,982 is independent of EP 4 receptor inhibitory activity; an alternative EP 4 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. |
| Databáze: | OpenAIRE |
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