Gram-negative bacteria are increasingly resistant to most available antibiotics, therefore discovery of new antibacterial agents against gram-negative pathogens such as Escherichia coli (EC) and Pseudomonas aeruginosa (PA) is urgently needed. LpxC, a Zn2+-dependent enzyme, is required for lipid A biosynthesis by Gram-negative pathogens. Consequently the search for potent LpxC inhibitors as potential antibacterial agents has received a great deal of attention. To date, most potent LpxC inhibitors use a hydroxamic acid as the zinc-binding group (ZBG). Our goal is to discover novel LpxC inhibitors with a non-hydroxamic acid ZBG, which may have improved safety profiles. Using a combination of structure-based design and HTS approaches, several series of novel LpxC inhibitors were discovered with a phosphonic acid ZBG. Key phosphonate LpxC inhibitors were identified that exhibit IC50 &lt;10 nM against both EC and PA LpxC enzymes, and demonstrated whole cell antibacterial activity. The design, synthesis and evaluation of these novel inhibitors will be presented.

Discovery of phosphonic acid containing LpxC inhibitors as broad spectrum antibacterial agents

249th National Meeting (2015)

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