Novel siderophore conjugated analogs of the natural product, lactivicin, were designed, guided by X-ray crystallography of a covalent complex of a lactivicin derivative with Pseudomonas aeruginosa (Pae) Penicillin Binding Protein 3 (PBP3). Analogs bearing a variety of sideophore mimicking groups extending into open regions of the active site were synthesized and evaluated. The targeted analogs exhibited Minimum Inhibitory Concentrations (MIC) against pathogenic Gram-negative organisms: Pae (0.5 - 32 �g/mL), Klebsiella pneumoniae (0.5 � 32 �g/ mL), Acinetobacter baumaunii (0.06 � 32 �g/mL), and Escherichia coli (0.25 � 2 �g/mL) and potent inhibition of Pae PBP1a, 1b and PBP3 (IC50 0.03 � 2.5 �M). A lead compound employing a novel siderophore mimic, 3,4-dihydroxyphthalimide, displayed enhanced Gram-negative inhibition and useful pharmacokinetics in rat.

Synthesis of siderophore conjugated Lactivicin compounds with activity against gram-negative pathogens

245th National Meeting (2013)

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