9ENG

Structure of K.pneumoniae LpxH in complex with EBL-3218

This is a non-PDB format compatible entry.

Summary for 9ENG

• Entry DOI: 10.2210/pdb9eng/pdb
• Descriptor: UDP-2,3-diacylglucosamine hydrolase, MANGANESE (II) ION, ~{N}-[4-[4-[3,5-bis(chloranyl)phenyl]piperazin-1-yl]sulfonylphenyl]-3-(methylsulfonylamino)benzamide, ... (4 entities in total)
• Functional Keywords: lipid a biosynthesis pathway endotoxin udp-diacyl-glucosamine lipid x gram-negative bacteria antibiotic lipopolysaccharides, hydrolase
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 28702.33

Authors

Sooriyaarachchi, S.,Bergfors, T.,Jones, T.A.,Mowbray, S.L. (deposition date: 2024-03-12, release date: 2024-09-18, Last modification date: 2025-02-19)

Primary citation

Benediktsdottir, A.,Sooriyaarachchi, S.,Cao, S.,Ottosson, N.E.,Lindstrom, S.,Lundgren, B.,Kloditz, K.,Lola, D.,Bobileva, O.,Loza, E.,Hughes, D.,Jones, T.A.,Mowbray, S.L.,Zamaratski, E.,Sandstrom, A.,Karlen, A.
Design, synthesis, and in vitro biological evaluation of meta-sulfonamidobenzamide-based antibacterial LpxH inhibitors.
Eur.J.Med.Chem., 278:116790-116790, 2024

PubMed Abstract: New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N-methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the N-methyl group when shifting the ortho-N-methyl-sulfonamide to the meta-position. This discovery led to the synthesis of meta-sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the meta-sulfonamidobenzamide analogs differ from those of the previously reported ortho analogs. Overall, our study has identified meta-sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs.

PubMed: 39236497
DOI: 10.1016/j.ejmech.2024.116790

Experimental method

X-RAY DIFFRACTION (2.2 Å)