Using membrane perturbing small molecules to target chronic persistent infections.

After antibiotic treatment, a subpopulation of bacteria often remains and can lead to recalcitrant infections. This subpopulation, referred to as persisters, evades antibiotic treatment through numerous mechanisms such as decreased uptake of small molecules and slowed growth. Membrane perturbing small molecules have been shown to eradicate persisters as well as render these populations susceptible to antibiotic treatment. Chemotype similarities have emerged suggesting amphiphilic heteroaromatic compounds possess ideal properties to increase membrane fluidity and such molecules warrant further investigation as effective agents or potentiators against persister cells.

Synthesis and biological evaluation of an antibacterial azaborine retinoid isostere.

Our continued synthetic interest in this class of retinoids, CD437 and its analogs, against methicillin-resistant Staphylococcus aureus (MRSA) has brought us to explore further isosteric substitutions within the scaffold. Although our previous findings have shown promising activity against gram-positive pathogens, their therapeutic viability remained an issue. Specifically, through preliminary analysis, our best performing compound, analog 2, displayed low solubility within serum as well as high affinity for retinoid binding proteins with a concentration dependent relationship. To circumvent this issue, we proposed a class of analogs containing an azaborine substitution in place of the naphthalene moiety. 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 cancer research but to the best of our knowledge has yet to be applied to antibiotics. Herein, we describe the synthesis of the desired analogs, antimicrobial activity, and surprising physiochemical properties.