AUTHOR=Zore Matej , Gilbert-Girard Shella , San-Martin-Galindo Paola , Reigada Inés , Hanski Leena , Savijoki Kirsi , Fallarero Adyary , Yli-Kauhaluoma Jari , Patel Jayendra Z. 

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

JOURNAL=Frontiers in Microbiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.926170

DOI=10.3389/fmicb.2022.926170

ISSN=1664-302X

ABSTRACT=<p>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 <italic>Staphylococcus aureus</italic> and identified five active compounds. Among them, etrasimod (APD334), an investigational drug for the treatment of ulcerative colitis, displayed the best inhibitory activity against <italic>S. aureus</italic> 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 <italic>S. aureus</italic> strains, <italic>S. epidermidis</italic>, and <italic>Enterococcus faecalis</italic>, with a minimum inhibitory concentration (MIC) ranging from 5 to 10 μM (2.3–4.6 μg/mL). However, no inhibition of viability was observed against Gram-negative bacteria <italic>Acinetobacter baumannii</italic>, <italic>Escherichia coli</italic>, and <italic>Pseudomonas aeruginosa</italic>, showing that etrasimod preferably acts against Gram-positive bacteria. On the other hand, etrasimod was shown to inhibit quorum sensing (QS) signaling in <italic>Chromobacterium violaceum</italic>, 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 <italic>S. aureus</italic>, thus showing potential to be used in antibiotic combination therapy. Finally, no <italic>in vitro</italic> 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.</p>