In collaboration with the Mylonakis lab at Brown University, we have demonstrated the activity of the synthetic retinoid, CD437, against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) as well as their membrane-targeting mechanism of action. Although CD437 and subsequent analogs have shown promising activity against gram-positive pathogens, their broad-spectrum and therapeutic viability remained unexplored. To further analyze these two areas of interest, we first appended alkylamines to the phenol moieties, which was a previously described method of expanding activity of membrane disruptors to Gram-negative species. Additionally, through preliminary analysis, our best performing analog, Analog 2, displayed low solubility within serum as well as high affinity for retinoid binding proteins with a concentration dependent relationship. To improve the solubility and decrease binding affinity, we proposed a class of analogs containing an azaborine substitution for the naphthalene ring. Azaborines have a nitrogen-boron bond substituting a carbon-carbon double bond that alters the electronics of the parent scaffold. This motif has been explored successfully in both cancer and agricultural research but has yet to be applied to antibiotics. We hypothesize that the alkylamine addition as well as the isosteric substitution may be efficient in broadening its activity as well as reducing the affinity to retinoid binding proteins thereby improving its therapeutic index.

Exploration of a synthetic retinoid scaffold for the treatment of persistent MRSA infections

ACS Fall 2021

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