7S04

1-deoxy-D-xylulose 5-phosphate reductoisomerase (IspC) from Acinetobacter baumannii in complex with FR900098, NADPH, and a magnesium ion

Summary for 7S04

• Entry DOI: 10.2210/pdb7s04/pdb
• Descriptor: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, 3-[ethanoyl(hydroxy)amino]propylphosphonic acid, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: isoprenoid biosynthesis, inhibitor, complex, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 1
• Total formula weight: 45062.50

Authors

Noble, S.M.,Ball, H.S.,Couch, R.D. (deposition date: 2021-08-28, release date: 2021-11-03, Last modification date: 2023-10-18)

Primary citation

Ball, H.S.,Girma, M.B.,Zainab, M.,Soojhawon, I.,Couch, R.D.,Noble, S.M.
Characterization and Inhibition of 1-Deoxy-d-Xylulose 5-Phosphate Reductoisomerase: A Promising Drug Target in Acinetobacter baumannii and Klebsiella pneumoniae .
Acs Infect Dis., 7:2987-2998, 2021

PubMed Abstract: The ESKAPE pathogens comprise a group of multidrug-resistant bacteria that are the leading cause of nosocomial infections worldwide. The prevalence of antibiotic resistant strains and the relative ease by which bacteria acquire resistance genes highlight the continual need for the development of novel antibiotics against new drug targets. The methylerythritol phosphate (MEP) pathway is an attractive target for the development of new antibiotics. The MEP pathway governs the synthesis of isoprenoids, which are key lipid precursors for vital cell components such as ubiquinone and bacterial hopanoids. Additionally, the MEP pathway is entirely distinct from the corresponding mammalian pathway, the mevalonic acid (MVA) pathway, making the first committed enzyme of the MEP pathway, 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC), an attractive target for antibiotic development. To facilitate drug development against two of the ESKAPE pathogens, and , we cloned, expressed, purified, and characterized IspC from these two Gram-negative bacteria. Enzyme inhibition assays using IspC from these two pathogens, and compounds fosmidomycin and FR900098, indicate IC values ranging from 19.5-45.5 nM. Antimicrobial susceptibility tests with these inhibitors reveal that is susceptible to FR900098, whereas is susceptible to both compounds. Finally, to facilitate structure-based drug design of inhibitors targeting IspC, we determined the 2.5 Å crystal structure of IspC from in complex with inhibitor FR900098, and cofactors NADPH and magnesium.

PubMed: 34672535
DOI: 10.1021/acsinfecdis.1c00132

Experimental method

X-RAY DIFFRACTION (2.52 Å)