29AH

Crystal structure of PaLpxC complexed with compound 6

This is a non-PDB format compatible entry.

Summary for 29AH

• Entry DOI: 10.2210/pdb29ah/pdb
• Descriptor: UDP-3-O-acyl-N-acetylglucosamine deacetylase, ZINC ION, 4-[(2~{R})-1-(2-fluoranylethylamino)-3-[4-[2-[4-(morpholin-4-ylmethyl)phenyl]ethynyl]phenyl]propan-2-yl]-5-oxidanyl-1~{H}-pyrimidin-6-one, ... (4 entities in total)
• Functional Keywords: lpxc, metalloprotease, antibiotic, inhibitor
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 1
• Total formula weight: 33702.60

Authors

Beaumont, E.J.,Cade, I.,Kopec, J.,Martin, D. (deposition date: 2026-03-03, release date: 2026-07-29, Last modification date: 2026-08-26)

Primary citation

Martin, D.P.,Teng, M.,Nammalwar, B.,Perez, C.,Li, X.,Munguia, J.,Taganov, K.,Fan, J.,Agarwalla, S.,Lonergan, D.,Tomaras, A.P.,Zimmerman, Z.,Puerta, D.T.
Discovery and Optimization of Novel Nonhydroxamate LpxC Inhibitors for the Treatment of Multidrug-Resistant Gram-Negative Infections.
J.Med.Chem., 69:18692-18704, 2026

PubMed Abstract: This report summarizes the discovery and optimization of a novel series of nonhydroxamate inhibitors targeting LpxC, a Zn2+-dependent hydrolase that is essential for the survival of Gram-negative bacteria. Beginning with a 5-hydroxypyrimidin-4-one metal-binding pharmacophore, structure-based approaches were utilized to generate a series of potent inhibitors that exhibited activity against a wide variety of Enterobacterales, including both susceptible and multidrug-resistant pathogens, and efficacy in murine thigh infection models. These novel compounds were evaluated in a rat model of cardiovascular toxicity to demonstrate the safety of the scaffold relative to another LpxC inhibitor that proved unsuccessful in Phase I clinical trials. A variety of inhibitors with potent in vivo efficacy and no hemodynamic effects were identified, which constituted an initial suite of potential development candidates.

PubMed: 42593942
DOI: 10.1021/acs.jmedchem.6c01036

Experimental method

X-RAY DIFFRACTION (2.2 Å)