PDBsum entry 6b1f

Hydrolase/hydrolase inhibitor

PDB id: 6b1f

Contents

Protein chains

268 a.a.

Ligands

C8Y ×2

CIT

EDO ×3

Waters ×495

References listed in PDB file

Key reference

• Title: Strategic approaches to overcome resistance against gram-Negative pathogens using β-Lactamase inhibitors and β-Lactam enhancers: activity of three novel diazabicyclooctanes wck 5153, Zidebactam (wck 5107), And wck 4234.
• Authors: K.M.Papp-Wallace, N.Q.Nguyen, M.R.Jacobs, C.R.Bethel, M.D.Barnes, V.Kumar, S.Bajaksouzian, S.D.Rudin, P.N.Rather, S.Bhavsar, T.Ravikumar, P.K.Deshpande, V.Patil, R.Yeole, S.S.Bhagwat, M.V.Patel, F.Van den akker, R.A.Bonomo.
• Ref.: J Med Chem, 2018, 61, 4067-4086. [DOI no: 10.1021/acs.jmedchem.8b00091]
• PubMed id: 29627985
• DOI number: 10.1021/ACS.JMEDCHEM.8B00091

Abstract

Limited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram-negative bacteria possessing broad-spectrum β-lactamases. The design of novel β-lactamase inhibitors is of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1-3, respectively), were synthesized and biochemically characterized against clinically important bacteria. Compound 3 inhibited class A, C, and D β-lactamases with unprecedented k₂/ K values against OXA carbapenemases. Compounds 1 and 2 acylated class A and C β-lactamses rapidly but not the tested OXAs. Compounds 1-3 formed highly stable acyl-complexes as demonstrated by mass spectrometry. Crystallography revealed that 1-3 complexed with KPC-2 adopted a "chair conformation" with the sulfate occupying the carboxylate binding region. The cefepime-2 and meropenem-3 combinations were effective in murine peritonitis and neutropenic lung infection models caused by MDR Acinetobacter baumannii. Compounds 1-3 are novel β-lactamase inhibitors that demonstate potent cross-class inhibition, and clinical studies targeting MDR infections are warranted.