Non-Nucleoside Inhibitors of BasE, an Adenylating Enzyme in the Siderophore Biosynthetic Pathway of the Opportunistic Pathogen Acinetobacter baumannii

• Published in: Journal of medicinal chemistry 2013-03, Vol.56 (6), p.2385-2405
• Main Authors: Neres, João, Engelhart, Curtis A, Drake, Eric J, Wilson, Daniel J, Fu, Peng, Boshoff, Helena I, Barry, Clifton E, Gulick, Andrew M, Aldrich, Courtney C
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii - drug effects; Acinetobacter baumannii - enzymology; Acinetobacter baumannii - metabolism; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Microbial Sensitivity Tests; Models, Molecular; Protein Conformation; Siderophores - biosynthesis; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301709s

Siderophores are small-molecule iron chelators produced by bacteria and other microorganisms for survival under iron limiting conditions such as found in a mammalian host. Siderophore biosynthesis is essential for the virulence of many important Gram-negative pathogens including Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. We performed high-throughput screening against BasE, which is involved in siderophore biosynthesis in A. baumannii, and identified 6-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid 15. Herein we report the synthesis, biochemical, and microbiological evaluation of a systematic series of analogues of the HTS hit 15. Analogue 67 is the most potent analogue with a K D of 2 nM against BasE. Structural characterization of the inhibitors with BasE reveals that they bind in a unique orientation in the active site, occupying all three substrate binding sites, and thus can be considered as multisubstrate inhibitors. These results provide a foundation for future studies aimed at increasing both enzyme potency and antibacterial activity.