Synthesis andantibacterial profiling of new derivatives of an immunomodulatory drug

What is it about?

Our earlier work revealed that etrasimod, a small molecule drug developed for the treatment of ulcerative cholitis and other autoimmune diseases, bears antibacterial activity againsst gram-positive bacteria. In this work, new chemical derivatives were designed and synthesized based on the etrasimod structure, in order to gain better understanding which features in the molecular structure contribute to the antibacterial activity. To narrow the translational gap between in vitro antibacterial assays and treatment settings in an infected organism, an infection model was established in a nematode Caenorhabditis elegans: the worms were infected with Staphylococcus aureus and used for in vivo efficacy evaluation of etrasimod and the most potent derivative. Using bacterial load as an endpoint, these compounds were found to efficiently suppress the in vivo infection of both S. aureus reference strain and meticillin-resistent S. aureus (MRSA) strain.Our earlier work revealed that etrasimod, a small molecule drug developed for the treatment of ulcerative cholitis and other autoimmune diseases, bears antibacterial activity againsst gram-positive bacteria. In this work, new chemical derivatives were designed and synthesized based on the etrasimod structure, in order to gain better understanding which features in the molecular structure contribute to the antibacterial activity. To narrow the translational gap between in vitro antibacterial assays and treatment settings in an infected organism, an infection model was established in a nematode Caenorhabditis elegans: the worms were infected with Staphylococcus aureus and used for in vivo efficacy evaluation of etrasimod and the most potent derivative. Using bacterial load as an endpoint, these compounds were found to efficiently suppress the in vivo infection of both S. aureus reference strain and meticillin-resistent S. aureus (MRSA) strain.

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Why is it important?

Finding new antibacterial agents is of paramount importance to tackle the fading efficacy of currently available antibiotics. Antibiotic discovery is challenged by the poor predictive value of in vitro experimentation for clinical efficacy, and therefore ethically sustainable, low-cost in vivo models such as C. elegans can offer invaluable help for prioritizing candidate compounds for further in vivo evaluation.Finding new antibacterial agents is of paramount importance to tackle the fading efficacy of currently available antibiotics. Antibiotic discovery is challenged by the poor predictive value of in vitro experimentation for clinical efficacy, and therefore ethically sustainable, low-cost in vivo models such as C. elegans can offer invaluable help for prioritizing candidate compounds for further in vivo evaluation.

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