Design and synthesis of etrasimod derivatives as potent antibacterial agents against Gram-positive bacteria

Abstract

The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents. Inspired by our recent report on the antibacterial activity of etrasimod, an immunomodulating drug candidate, we prepared a series of etrasimod derivatives by varying substituents on the phenyl ring, altering the central tricyclic aromatic ring, and modifying the carboxyl group. From this series of compounds, indole derivative 24f was identified as the most potent antibacterial compound, with the minimum inhibitory concentration (MIC) values between 2.5 and 10 μM against various Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), S. epidermidis and enterococci. Moreover, 24f exhibited rapid bactericidal activity against S. aureus, low toxicity and hemolytic activity, and a synergistic effect with gentamicin against S. aureus, MRSA, and Enterococcus faecalis. Furthermore, it was shown that neither etrasimod nor 24f affects S. aureus cell membranes. Importantly, 24f did not induce resistance in S. aureus, representing a significant improvement compared to etrasimod. Finally, the antibacterial activity of etrasimod and 24f against S. aureus and MRSA was confirmed in vivo in a Caenorhabditis elegans infection model. Taken together, our study highlights the value of etrasimod and its derivatives as potential antibacterial candidates for combating infections caused by Gram-positive bacteria.

Keywords: Antibacterial activity; Derivatives; Etrasimod; MRSA; Staphylococcus aureus.