9OZG

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

This is a non-PDB format compatible entry.

Summary for 9OZG

• Entry DOI: 10.2210/pdb9ozg/pdb
• Descriptor: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, [(1E)-3-(3,5-dichloro-N-hydroxybenzamido)prop-1-en-1-yl]phosphonic acid, ... (6 entities in total)
• Functional Keywords: inhibitor, reductoisomerase, oxidoreductase
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 1
• Total formula weight: 45439.72

Authors

Girma, M.B.,Ball, H.S.,Belcher Dufrisne, M.,Lee, S.H.,Soojhawon, I.,Noble, S.M.,Dowd, C.S.,Couch, R.D. (deposition date: 2025-06-05, release date: 2026-03-25)

Primary citation

Girma, M.,Dufrisne, M.B.,Sehgal, A.,Dailey, A.,Heidel, K.,Bague, D.,Wang, X.,Bartholomew, L.,Beck, R.,Kirby, S.,Ball, H.,Zainab, M.,Lee, S.H.,Soojhawon, I.,Noble, S.M.,Dowd, C.S.,Couch, R.D.
Structure-Activity Relationships among Inhibitors of Acinetobacter baumannii and Klebsiella pneumoniae 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase (DXR/IspC) - A Promising Target for Antibiotic Development.
Acs Infect Dis., 2026

PubMed Abstract: Antimicrobial resistance (AMR) is a critical global health crisis, responsible for nearly 5 million deaths in 2019 and projected to impose up to $100 trillion in economic costs by 2050. To address this threat, we are developing new antibiotics targeting the methylerythritol phosphate (MEP) pathway in and , major nosocomial pathogens. Our efforts focus on 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC/DXR), the committed enzyme in MEP-mediated isoprenoid biosynthesis and absent in humans, making it an attractive therapeutic target. Natural products such as fosmidomycin (FOS) and FR900098 (FR) inhibit IspC but exhibit poor bioavailability. To improve drug-like properties, we synthesized FOS analogs and analyzed their structure-activity relationships (SARs) against recombinant Ab- and Kp-IspC, alongside in vitro susceptibility assays. The most potent analogs, α,β-unsaturated compounds and , inhibited Ab-IspC (AbIspC) with IC values of 0.047 μM and 0.029 μM, and Kp-IspC (KpIspC) with 0.194 μM and 0.054 μM, respectively. These showed MICs of 64 μg/mL for and 512 μg/mL for . A prodrug series (-) demonstrated enhanced activity, with compound exhibiting MICs from 0.25 to 32 μg/mL against . X-ray crystallography of Ab-IspC with selected analogs (, , ) at 2.0 Å resolution provides structural insights to guide future IspC inhibitor optimization.

PubMed: 41816984
DOI: 10.1021/acsinfecdis.5c00875

Experimental method

X-RAY DIFFRACTION (2 Å)