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Updated: Dec 24, 2025

Quadruple-Checkerboard: A Modification of the Three-Dimensional Checkerboard for Studying Drug Combinations
Published on: July 24, 2021
Potential combinations of endocannabinoid/endocannabinoid-like compounds and antibiotics against
Mark Feldman1, Reem Smoum2, Raphael Mechoulam2
1Biofilm Research Laboratory, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Abstract:
Infections caused by antibiotic-resistant strains of Staphylococcus aureus have reached epidemic proportions globally. Our previous study showed antimicrobial effects of anandamide (AEA) and arachidonoyl serine (AraS) against methicillin (MET)-resistant S. aureus (MRSA) strains, proposing the therapeutic potential of these endocannabinoid/endocannabinoid-like (EC/EC-like) agents for the treatment of MRSA. Here, we investigated the potential synergism of combinations of AEA and AraS with different types of antibiotics against MRSA grown under planktonic growth or biofilm formation. The most effective combinations under planktonic conditions were mixtures of AEA and ampicillin (AMP), and of AraS and gentamicin (GEN). The combination with the highest synergy in the biofilm formation against all tested bacterial strains was AEA and MET. Moreover, the combination of AraS and MET synergistically caused default of biofilm formation. Slime production of MRSA was also dramatically impaired by AEA or AraS combined with MET. Our data suggest the novel potential activity of combinations of EC/EC-like agents and antibiotics in the prevention of MRSA biofilm formation.
Insights
This study explores combining endocannabinoid agents anandamide (AEA) and arachidonoyl serine (AraS) with antibiotics against antibiotic-resistant Staphylococcus aureus. Certain combinations show significant synergy, particularly in preventing bacterial biofilm formation.
Area of Science:
- Microbiology
- Pharmacology
- Biochemistry
Background:
- Antibiotic-resistant Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), poses a global health threat.
- Endocannabinoid/endocannabinoid-like (EC/EC-like) agents anandamide (AEA) and arachidonoyl serine (AraS) previously demonstrated antimicrobial effects against MRSA.
Purpose of the Study:
- To investigate the synergistic potential of combining AEA and AraS with various antibiotics against MRSA.
- To evaluate these combinations in both planktonic and biofilm growth conditions.
Main Methods:
- MRSA strains were cultured under planktonic and biofilm conditions.
- Combinations of AEA and AraS with antibiotics (ampicillin, gentamicin, methicillin) were tested for synergistic effects.
- Slime production and biofilm formation were assessed.
Main Results:
- Anandamide (AEA) and ampicillin (AMP), and arachidonoyl serine (AraS) and gentamicin (GEN) showed synergy in planktonic cultures.
- AEA and methicillin (MET) exhibited the highest synergy against MRSA biofilms.
- AraS and MET synergistically inhibited biofilm formation and impaired slime production.
Conclusions:
- Combinations of EC/EC-like agents and antibiotics demonstrate significant synergistic activity against MRSA.
- These combinations show promise in preventing MRSA biofilm formation, a critical factor in persistent infections.
- This research suggests a novel therapeutic strategy for combating MRSA infections.
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