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Biosensor for Detection of Antibiotic Resistant Staphylococcus Bacteria
Published on: May 8, 2013
Prostaglandin E2 Receptor Antagonist with Antimicrobial Activity against Methicillin-Resistant Staphylococcus aureus
Mélanie A C Ikeh1, Paul L Fidel1, Mairi C Noverr2,3
1Department of Oral and Craniofacial Biology, Dental School, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Abstract:
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 E2 (PGE2) plays a key role in the lethal inflammatory response during polymicrobial IAI using a mouse model of infection. In studies designed to uncover key PGE2 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 EP4 receptor antagonist L-161,982 had direct growth-inhibitory effects on S. aureusin vitro at the physiological concentration required to block the PGE2 interaction with EP4 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 EP4 receptor inhibitory activity; an alternative EP4 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.
Insights
The EP4 receptor antagonist L-161,982 shows direct antimicrobial effects against Staphylococcus aureus, including MRSA. This compound reduces bacterial burden and improves survival in mouse models of infection, offering a potential new therapy.
Area of Science:
- Microbiology
- Immunology
- Pharmacology
Background:
- Polymicrobial intra-abdominal infections (IAI) involving Candida albicans and Staphylococcus aureus are linked to high mortality.
- Prostaglandin E2 (PGE2), an immunomodulatory eicosanoid, plays a critical role in the lethal inflammatory response during polymicrobial IAI.
- Investigating PGE2 biosynthesis and signaling components is crucial for understanding and treating these infections.
Purpose of the Study:
- To identify key components in PGE2 signaling involved in lethal inflammatory responses during polymicrobial IAI.
- To evaluate the antimicrobial and therapeutic potential of EP4 receptor antagonists against S. aureus.
Main Methods:
- Prescreening of selective eicosanoid enzyme inhibitors and receptor antagonists for antimicrobial activity against C. albicans and S. aureus.
- In vitro testing of L-161,982 for growth inhibition, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) against S. aureus.
- Assessment of L-161,982's effect on S. aureus biofilm formation and preformed biofilms.
- In vivo studies using mouse models of S. aureus monoinfection and coinfection with C. albicans to evaluate survival and bioburden reduction.
Main Results:
- The EP4 receptor antagonist L-161,982 demonstrated direct in vitro growth-inhibitory effects on both methicillin-sensitive and methicillin-resistant S. aureus (MRSA).
- L-161,982 exhibited significant activity against S. aureus biofilms, inhibiting formation and eradicating mature biofilms.
- In vivo, L-161,982 treatment significantly reduced MRSA bioburden and enhanced survival in mice, and protected against lethal coinfection.
- The antimicrobial activity of L-161,982 was independent of its EP4 receptor antagonist function.
Conclusions:
- L-161,982 possesses potent antimicrobial activity against MRSA, independent of its EP4 receptor antagonism.
- L-161,982 shows promise as a therapeutic agent for S. aureus mono-infections and polymicrobial infections involving S. aureus.
- This compound represents a potential therapeutic alternative for improving outcomes in MRSA-associated infections.
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