title: Non-nucleoside inhibitors of BasE, an adenylating enzyme in the siderophore biosynthetic pathway of the opportunistic pathogen Acinetobacter baumannii.
abstract: 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 KD 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.
authors: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, USA.
authors: João
authors: J
authors: Neres
authors: Curtis A
authors: CA
authors: Engelhart
authors: Eric J
authors: EJ
authors: Drake
authors: Daniel J
authors: DJ
authors: Wilson
authors: Peng
authors: P
authors: Fu
authors: Helena I
authors: HI
authors: Boshoff
authors: Clifton E
authors: CE
authors: Barry
authors: Andrew M
authors: AM
authors: Gulick
authors: Courtney C
authors: CC
authors: Aldrich
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011487:Protein Conformation; D017262:Siderophores / Q000096:biosynthesis*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D017262:Siderophores