Abstract

As strains of drug resistant bacteria become more common, it is becoming increasingly necessary to synthesize novel compounds to overcome known resistance mechanisms. Natural products remain a robust source of novel bioactive molecules. Pseudopyronines, first isolated from Pseudomonas bacteria in 2002, are members of the α-pyrone class of antibiotics and have shown significant promise as natural product antibiotics. This work derivatizes the ɑ-pyrone core of short chain pseudopyronine analogs to probe the effects of L-amino acid methyl esters on antibiotic activity against Escherichia coli. The 4’ and 5’ carbons of the α-pyrone core will be substituted with various L-amino acid esters as these positions have previously been found to contribute heavily to biological activity. This is based on previous research which showed that the addition of bulky amino acid groups inhibited AcrAB-TolC efflux pumps, the “garbage chutes'' of the bacteria which are commonly overexpressed in many Gram-negative bacteria. This opens the potential for the synthesized molecules to be dosed adjuvantly with a known antibiotic. Each analog was tested for antibiotic activity in a cell death assay against Gram-negative and Gram-positive bacteria, as well as assessed for efflux inhibition potential via an AcrAB-TolC efflux pump assay.

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