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. An X-ray cocrystal structure of the leadcompound covalently bound in Pae PBP1a revealed a dual function of the siderophore as both a recognition element for active transport into the Gram-negative cell and enhanced potency through a productive aromatic-stacking interaction with Tyr733. The binding modes of lactivicin analogs and BAL30072 in X-ray cocrystal structures were compared. Differences observed in the susceptibility to �-lactamases of BAL30072 compared to lactivicin analogs support the hypothesis that placement of the siderophore sidechain opposite to the aminothiazole sidechain confers broader resistance to �-lactamase hydrolysis than placement of the siderophore proximal to the aminothiazole.

Siderophore conjugated lactivicin compounds with activity against gram-negative pathogens

245th National Meeting (2013)

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