Repurposing the Sphingosine-1-Phosphate Receptor Modulator Etrasimod as an Antibacterial Agent Against Gram-Positive Bacteria

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Zore , M , Gilbert-Girard , S , San-Martin-Galindo , P , Reigada , I , Hanski , L , Savijoki , K , Fallarero , A , Yli-Kauhaluoma , J & Patel , J 2022 , ' Repurposing the Sphingosine-1-Phosphate Receptor Modulator Etrasimod as an Antibacterial Agent Against Gram-Positive Bacteria ' , Frontiers in Microbiology , vol. 13 , 926170 . https://doi.org/10.3389/fmicb.2022.926170

Title: Repurposing the Sphingosine-1-Phosphate Receptor Modulator Etrasimod as an Antibacterial Agent Against Gram-Positive Bacteria
Author: Zore, Matej; Gilbert-Girard, Shella; San-Martin-Galindo, Paola; Reigada, Inés; Hanski, Leena; Savijoki, Kirsi; Fallarero, Adyary; Yli-Kauhaluoma, Jari; Patel, Jayendra
Contributor organization: Division of Pharmaceutical Chemistry and Technology
Pharmaceutical Design and Discovery group
Divisions of Faculty of Pharmacy
Division of Pharmaceutical Biosciences
The Academic Outreach Network
Helsinki One Health (HOH)
Drug Research Program
Explorations of Anti Infectives
Faculty of Pharmacy
Department of Food and Nutrition
Jari Yli-Kauhaluoma / Principal Investigator
Date: 2022-06-06
Language: eng
Number of pages: 13
Belongs to series: Frontiers in Microbiology
ISSN: 1664-302X
DOI: https://doi.org/10.3389/fmicb.2022.926170
URI: http://hdl.handle.net/10138/345850
Abstract: New classes of antibiotics are urgently needed in the fight against multidrug-resistant bacteria. Drug repurposing has emerged as an alternative approach to accelerate antimicrobial research and development. In this study, we screened a library of sphingosine-1-phosphate receptor (S1PR) modulators against Staphylococcus aureus and identified five active compounds. Among them, etrasimod (APD334), an investigational drug for the treatment of ulcerative colitis, displayed the best inhibitory activity against S. aureus when growing as free-floating planktonic cells and within biofilms. In follow-up studies, etrasimod showed bactericidal activity and drastic reduction of viable bacteria within 1 h of exposure. It also displayed a potent activity against other Gram-positive bacteria, including penicillin- and methicillin-resistant S. aureus strains, S. epidermidis, and Enterococcus faecalis, with a minimum inhibitory concentration (MIC) ranging from 5 to 10 mu M (2.3-4.6 mu g/mL). However, no inhibition of viability was observed against Gram-negative bacteria Acinetobacter baumannii, Escherichia coli, and Pseudomonas aeruginosa, showing that etrasimod preferably acts against Gram-positive bacteria. On the other hand, etrasimod was shown to inhibit quorum sensing (QS) signaling in Chromobacterium violaceum, suggesting that it may block the biofilm formation by targeting QS in certain Gram-negative bacteria. Furthermore, etrasimod displayed a synergistic effect with gentamicin against S. aureus, thus showing potential to be used in antibiotic combination therapy. Finally, no in vitro toxicity toward mammalian cells was observed. In conclusion, our study reports for the first time the potential of etrasimod as a repurposed antibacterial compound against Gram-positive bacteria.
Subject: BIOFILMS
EFFICACY
Gram-positive bacteria
RESISTANCE
SAFETY
SUSCEPTIBILITY
Staphylococcus aureus
antimicrobials
biofilms
etrasimod
repurposing
sphingosine-1-phosphate receptor modulators
11832 Microbiology and virology
317 Pharmacy
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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