Treatment of infections caused by highly resistant Gram-negative bacteria is a growing concern, especially since some strains are entirely resistant to all clinically available antibiotics; however, the development of novel compounds with broad spectrum activity has drastically slowed. Previously synthesized propargylglycine-based compounds with a biphenyl tail designed to target LpxC showed antibacterial activity against <i>Escherichia coli,</i> but only in mutants with TolC-mediated efflux knocked out. In an attempt to avoid efflux, several analogues have been designed with increased hydrophilicity. This change may also result in improved binding in the polar region of the LpxC active site, the enzyme that it potentially inhibited by these compounds. Specifically, a series of nine compounds with a variety of polar side chains and hydrophobic tails have been synthesized in good yield. Molecular docking was used to determine a docking score and key interactions within the LpxC active site. Synthesis of these potential antibacterial agents will be described, and results of bacterial growth studies will be discussed.

Synthesis of gram-negative antibacterial compounds with increased hydrophilicity to avoid TolC-mediated efflux

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