Targeting the Achilles’ Heel of Multidrug-Resistant Staphylococcus aureus by the Endocannabinoid Anandamide

Ronit Vogt Sionov*, Shreya Banerjee, Sergei Bogomolov, Reem Smoum, Raphael Mechoulam, Doron Steinberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Antibiotic-resistant Staphylococcus aureus is a major health issue that requires new therapeutic approaches. Accumulating data suggest that it is possible to sensitize these bacteria to antibiotics by combining them with inhibitors targeting efflux pumps, the low-affinity penicillin-binding protein PBP2a, cell wall teichoic acid, or the cell division protein FtsZ. We have previously shown that the endocannabinoid Anandamide (N-arachidonoylethanolamine; AEA) could sensitize drug-resistant S. aureus to a variety of antibiotics, among others, through growth arrest and inhibition of drug efflux. Here, we looked at biochemical alterations caused by AEA. We observed that AEA increased the intracellular drug concentration of a fluorescent penicillin and augmented its binding to membrane proteins with concomitant altered membrane distribution of these proteins. AEA also prevented the secretion of exopolysaccharides (EPS) and reduced the cell wall teichoic acid content, both processes known to require transporter proteins. Notably, AEA was found to inhibit membrane ATPase activity that is necessary for transmembrane transport. AEA did not affect the membrane GTPase activity, and the GTPase cell division protein FtsZ formed the Z-ring of the divisome normally in the presence of AEA. Rather, AEA caused a reduction in murein hydrolase activities involved in daughter cell separation. Altogether, this study shows that AEA affects several biochemical processes that culminate in the sensitization of the drug-resistant bacteria to antibiotics.

Original languageAmerican English
Article number7798
JournalInternational Journal of Molecular Sciences
Volume23
Issue number14
DOIs
StatePublished - 14 Jul 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors.

Keywords

  • Staphylococcus aureus
  • anandamide
  • antibiotic resistance
  • autolysins
  • drug sensitization
  • endocannabinoids
  • transmembrane transport
  • wall teichoic acid

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