PDBsum entry 6b1f

Hydrolase/hydrolase inhibitor

PDB id: 6b1f

Contents

Protein chains

268 a.a.

Ligands

C8Y ×2

CIT

EDO ×3

Waters ×495

PDB id:

6b1f

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure kpc-2 beta-lactamase complexed with wck 4234 by soaking

Structure:

Carbapenem-hydrolyzing beta-lactamase kpc. Chain: a, b. Synonym: carbapenem-hydrolyzing beta-lactamase kpc-1. Engineered: yes

Source:

Klebsiella pneumoniae. Organism_taxid: 573. Gene: bla, kpc, kpc1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.44Å R-factor: 0.151 R-free: 0.174

Authors:

F.Van Den Akker,N.Q.Nguyen

Key ref:

K.M.Papp-Wallace et al. (2018). 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. J Med Chem, 61, 4067-4086. PubMed id: 29627985 DOI: 10.1021/acs.jmedchem.8b00091

Date:

18-Sep-17 Release date: 01-Aug-18

Protein chains

Q9F663  (BLKPC_KLEPN) -  Carbapenem-hydrolyzing beta-lactamase KPC from Klebsiella pneumoniae

Seq: 293 a.a.

Struc: 268 a.a.

Enzyme reactions

• Enzyme class: E.C.3.5.2.6 - beta-lactamase.
• Pathway: Penicillin Biosynthesis and Metabolism
• Reaction: a beta-lactam + H2O = a substituted beta-amino acid
• Cofactor: Zn(2+)

DOI no: 10.1021/acs.jmedchem.8b00091

J Med Chem 61:4067-4086 (2018)

PubMed id: 29627985

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.

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.

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.