6B1H

Crystal structure KPC-2 beta-lactamase complexed with WCK 4234 by co-crystallization

Summary for 6B1H

• Entry DOI: 10.2210/pdb6b1h/pdb
• Related: 6B1F
• Descriptor: Carbapenem-hydrolyzing beta-lactamase KPC, (2S,5R)-1-formyl-5-[(sulfooxy)amino]piperidine-2-carbonitrile, SULFATE ION, ... (6 entities in total)
• Functional Keywords: inhibitor, complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 2
• Total formula weight: 57769.58

Authors

van den Akker, F.,Nhuyen, N.Q. (deposition date: 2017-09-18, release date: 2018-08-01, Last modification date: 2024-10-23)

Primary citation

Papp-Wallace, K.M.,Nguyen, N.Q.,Jacobs, M.R.,Bethel, C.R.,Barnes, M.D.,Kumar, V.,Bajaksouzian, S.,Rudin, S.D.,Rather, P.N.,Bhavsar, S.,Ravikumar, T.,Deshpande, P.K.,Patil, V.,Yeole, R.,Bhagwat, S.S.,Patel, M.V.,van den Akker, F.,Bonomo, R.A.
Strategic Approaches to Overcome Resistance against Gram-Negative Pathogens Using beta-Lactamase Inhibitors and beta-Lactam Enhancers: Activity of Three Novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234.
J. Med. Chem., 61:4067-4086, 2018

PubMed 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 k/ 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.

PubMed: 29627985
DOI: 10.1021/acs.jmedchem.8b00091

Experimental method

X-RAY DIFFRACTION (1.8 Å)