7TI2

Structure of KPC-2 bound to RPX-7063 at 1.75A

Summary for 7TI2

• Entry DOI: 10.2210/pdb7ti2/pdb
• Descriptor: Carbapenem-hydrolyzing beta-lactamase KPC, {(3R,7S)-2-hydroxy-3-[2-(thiophen-2-yl)acetamido]-2,3,4,7-tetrahydro-1,2-oxaborepin-7-yl}acetic acid, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: kpc-2, hydrolase
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 29998.48

Authors

Clifton, M.C.,Fairman, J.W.,Edwards, T.E.,Hecker, S.J. (deposition date: 2022-01-12, release date: 2022-10-12, Last modification date: 2024-10-30)

Primary citation

Raja Reddy, K.,Totrov, M.,Lomovskaya, O.,Griffith, D.C.,Tarazi, Z.,Clifton, M.C.,Hecker, S.J.
Broad-spectrum cyclic boronate beta-lactamase inhibitors featuring an intramolecular prodrug for oral bioavailability.
Bioorg.Med.Chem., 62:116722-116722, 2022

PubMed Abstract: Early efforts to broaden the spectrum and potency of cyclic boronic acid β-lactamase inhibitor vaborbactam included a series of 7-membered ring boronates. Exploration of stereoisomers and incorporation of heteroatoms allowed identification of the all-carbon cyclic boronate with substituents trans as the preferred core structure, showing inhibition of Class A and C enzymes. Crystal structures of one analog bound to important β-lactamase enzymes were obtained. When isolated under acidic conditions, these compounds spontaneously formed a neutral cyclic anhydride (intramolecular prodrug) which was shown to have much-improved oral bioavailability (52-69%) compared to the ring-opened carboxylate salt (9%).

PubMed: 35358864
DOI: 10.1016/j.bmc.2022.116722

Experimental method

X-RAY DIFFRACTION (1.75 Å)