7TI0

Structure of CTX-M-15 bound to RPX-7063 at 1.5A

Summary for 7TI0

• Entry DOI: 10.2210/pdb7ti0/pdb
• Descriptor: Beta-lactamase, {(3R,7S)-2-hydroxy-3-[2-(thiophen-2-yl)acetamido]-2,3,4,7-tetrahydro-1,2-oxaborepin-7-yl}acetic acid, SULFATE ION, ... (6 entities in total)
• Functional Keywords: ctx-m-15, antibiotic, hydrolase
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 28737.62

Authors

Clifton, M.C.,Abendroth, J.,Hecker, S.J.,Edwards, T.E. (deposition date: 2022-01-12, release date: 2022-05-18, Last modification date: 2024-10-09)

Primary citation

Reddy, K.R.,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 (1.5 Å)