Quorum sensing antagonists have been proposed as novel therapeutic agents in the fight against antibiotic resistant bacterial infections. A previous study has shown that a marine Gram-positive bacterium, Halobacillus salinus, produces a phenethylamide secondary metabolite that is capable of inhibiting quorum sensing controlled phenotypes in several Gram-negative reporter strains, including bioluminescence by the marine pathogen Vibrio harveyi, violacein production by Chromobacterium violaceum, and green fluorescence protein (GFP) biosynthesis in an engineered E. coli. A panel of diaryl phenethylamide analogs have been synthesized and biologically evaluated in the same sensor strains. Most of these analogs were more active than the natural product, with a di-fluoro substituted analog showing a 100-fold increase (EC50 88 μM to 800 nM) in its ability to inhibit bioluminescence in Vibrio harveyi. These compounds and the resulting structure-activity relationships are of interest for future studies and will be useful in guiding development of additional analogs with potential as novel anti-pathogenic agents.

Synthesis and biological evaluation of analogs of a bacterial secondary metabolite for antagonism of quorum sensing phenotypes

256th National Meeting (2018)

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